Indoles

ABSTRACT

The present invention is concerned with novel indol-3-yl-carbonyl-piperidine-benzopyrrolone, -benzoxazolone and -benzotriazole derivatives as V1a receptor antagonists, their manufacture, pharmaceutical compositions containing them and their use for the treatment of anxiety and depressive disorders and other diseases. In particular, the present invention is concerned with compounds of formula (I) 
                         
wherein X, Y and R 1  to R 10  are as described in the specification.

PRIORITY TO RELATED APPLICATION(S)

This application claims the benefit of European Patent Application No.06127307.4, filed Dec. 28, 2006, which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

Vasopressin is a 9 amino acid peptide mainly produced by theparaventricular nucleus of the hypothalamus. Three vasopressinreceptors, all belonging to the class I G-protein coupled receptors, areknown. The V1a receptor is expressed in the brain, liver, vascularsmooth muscle, lung, uterus and testis, the V1b or V3 receptor isexpressed in the brain and pituitary gland, the V2 receptor is expressedin the kidney where it regulates water excretion and mediates theantidiuretic effects of vasopressin.

In the periphery vasopressin acts as a neurohormone and stimulatesvasoconstriction, glycogenolysis and antidiuresis. In the brainvasopressin acts as a neuromodulator and is elevated in the amygdaladuring stress (Ebner, K., C. T. Wotjak, et al. (2002). “Forced swimmingtriggers vasopressin release within the amygdala to modulatestress-coping strategies in rats.” Eur J Neurosci 15(2): 384-8). The V1areceptor is extensively expressed in the brain and particularly inlimbic areas like the amygdala, lateral septum and hippocampus which areplaying an important role in the regulation of anxiety. Indeed V1aknock-out mouse show a reduction in anxious behavior in the plus-maze,open field and light-dark box (Bielsky, I. F., S. B. Hu, et al. (2003).“Profound Impairment in Social Recognition and Reduction in Anxiety-LikeBehavior in Vasopressin V1a Receptor Knockout Mice.”Neuropsychopharmacology). The downregulation of the V1a receptor usingantisense oligonucleotide injection in the septum also causes areduction in anxious behavior (Landgraf, R., R. Gerstberger, et al.(1995). “V1 vasopressin receptor antisense oligodeoxynucleotide intoseptum reduces vasopressin binding, social discrimination abilities, andanxiety-related behavior in rats.” Regul Pept 59(2): 229-39).

The V1a receptor is also mediating the cardiovascular effects ofvasopressin in the brain by centrally regulating blood pressure andheart rate in the solitary tract nucleus (Michelini, L. C. and M. Morris(1999). “Endogenous vasopressin modulates the cardiovascular responsesto exercise.” Ann N Y Acad Sci 897: 198-211). In the periphery itinduces the contraction of vascular smooth muscles and chronicinhibition of the V1a receptor improves hemodynamic parameters inmyocardial infarcted rats (Van Kerckhoven, R., I. Lankhuizen, et al.(2002). “Chronic vasopressin V(1A) but not V(2) receptor antagonismprevents heart failure in chronically infarcted rats.” Eur J Pharmacol449(1-2): 135-41).

SUMMARY OF THE INVENTION

The present invention provides novelindol-3-yl-carbonyl-piperidine-benzopyrrolone, -benzoxazolone and-benzotriazole derivatives as V1a receptor antagonists, theirmanufacture, pharmaceutical compositions containing them and their usefor the treatment of anxiety and depressive disorders and otherdiseases.

In particular, the present invention provides compounds of formula (I)

wherein

-   X is CH₂, and Y is C═O,-   X is O, and Y is C═O, or-   X—Y is N═N;-   R¹ is H,    -   C₁₋₁₂-alkyl, optionally substituted with CN or OH,    -   C₁₋₆-haloalkyl,    -   C₂₋₁₂-alkenyl,    -   —(CR^(i)R^(ii))_(m)—R^(a),        -   wherein R^(i) and R^(ii) are independently from each other            H, methyl, or ethyl;        -   wherein m is from 0 to 4;        -   wherein R^(a) is            -   phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered                heterocycloalkyl                -   or 3 to 7-membered cycloalkyl,                -    which are optionally substituted with one or more                    A, or            -   —NR^(b)R^(c), wherein R^(b) and R^(c) are each                independently                -   hydrogen,                -   hydroxy,                -   C₁₋₆-alkyl,                -   —S(O)₂—C₁₋₆-alkyl, or                -   —C(O)—C₁₋₆-alkyl,    -   —(CR^(iii)R^(iv))_(n)—C(O)R^(d),        -   wherein R^(iii) and R^(iv) are each independently H, methyl,            or ethyl;        -   wherein n is from 0 to 4;        -   wherein R^(d) is            -   C₁₋₆-alkoxy,            -   —NR^(e)R^(f), wherein R^(e) and R^(f) are each                independently                -   hydrogen,                -   C₁₋₆-alkyl, or                -   —(C₂₋₆-alkylene)-NR^(g)R^(h); wherein R^(g) and                    R^(h) are each independently hydrogen, C₁₋₆-alkyl,                    or —C(O)O—C₁₋₆-alkyl, or            -   phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered                heterocycloalkyl                -   or 3 to 7-membered cycloalkyl,                -    which are optionally substituted with one or more                    A,    -   —S(O)₂-phenyl, wherein phenyl is optionally substituted with one        or more halo, C₁₋₆-haloalkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,        C₁₋₆-haloalkoxy, nitro, hydroxy or cyano;    -   —S(O)₂—C₁₋₆-alkyl,    -   —S(O)₂N(C₁₋₆-alkyl)₂, or    -   —S(O)₂NH(C₁₋₆-alkyl);-   A is halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl,    C₁₋₆-cyanoalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, —S(O)₀₋₂C₁₋₆-alkyl,    nitro, hydroxy, cyano, —(C₁₋₆-alkylene)-O—C₁₋₆-alkyl,    —(C₁₋₆-alkylene)-O—C₁₋₆-haloalkyl, —(C₁₋₆-alkylene)-OR′″,    —C(O)OC₁₋₆-alkyl, —C(O)C₁₋₆-alkyl, —C(O)OR′″, —C(O)R′″, —C(O)NR′R″,    —S(O)₂NR′R″, —(CH₂)_(x)—NR′R″, —(CH₂)_(x)—NR′C(O)—C₁₋₆-alkyl,    —(CH₂)_(x)—NR′S(O)₂—C₁₋₆-alkyl, —(CH₂)_(x)—C₃₋₆-cycloalkyl, or    —(CH₂)_(x)—R′″,    -   wherein x is from 0 to 4,    -   R′ and R″ are each independently H or C₁₋₆-alkyl, or    -   R′ and R″ together with the nitrogen to which they are bound        form a 5 or 6-membered heterocycle comprising one or two        heteroatoms selected from N, O and S, and    -   R′″ is phenyl or 5- to 6-membered heteroaryl, optionally        substituted with one, two, or three halo, C₁₋₆-haloalkyl,        C₁₋₆-alkyl, or C₁₋₆-alkoxy,-   R² is hydrogen,    -   C₁₋₆-alkyl, or    -   —C(O)R^(n), wherein R^(n) is        -   C₁₋₆-alkyl,        -   3 to 7-membered heterocycloalkyl, optionally substituted            with one, two or three C₁₋₆-alkyl, —C(O)O—C₁₋₆-alkyl, or            —S(O)₂—C₁₋₆-alkyl, or        -   NR^(j)R^(k), wherein R^(j) and R^(k) are each independently            -   hydrogen,            -   C₁₋₆-alkyl, or            -   —(C₂₋₆-alkylene)-NR^(l)R^(m); wherein R^(l) and R^(m)                are each independently hydrogen, C₁₋₆-alkyl, or                —C(O)O—C₁₋₆-alkyl; or-   R¹ together with R² forms a 5- to 6-membered heterocycloalkyl moiety    fused to the indole core, bearing one or two ring heteroatoms    selected from N, S and O, and being optionally substituted by one or    more A;-   R³, R⁴, R⁵, R⁶ are each independently hydrogen, halo, C₁₋₆-alkyl,    halo-C₁₋₆-alkyl, C₁₋₆-alkoxy or C₁₋₆-haloalkoxy;-   R⁷, R⁸, R⁹, R¹⁰ are each independently hydrogen, halo, C₁₋₆-alkyl,    halo-C₁₋₆-alkyl, C₁₋₆-alkoxy or C₁₋₆-haloalkoxy;-   or a pharmaceutically acceptable salt thereof,-   with the proviso that compounds wherein R¹, R², R³, R⁴, R⁵ and R⁶    are all simultaneously hydrogen are excluded.

The compounds of formula (I) can be manufactured by the methods givenbelow, by the methods given in the examples or by analogous methods.Appropriate reaction conditions for the individual reaction steps areknown to a person skilled in the art. Starting materials are eithercommercially available or can be prepared by methods analogous to themethods given below, by methods described in references cited in thetext or in the examples, or by methods known in the art.

The compounds of formula (I) possess pharmaceutical activity, inparticular they are modulators of V1a receptor activity. Moreparticular, the compounds are antagonists of the V1a receptor. Suchantagonists are useful as therapeutics in the conditions ofdysmenorrhea, hypertension, chronic heart failure, inappropriatesecretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessivecompulsive disorder, anxiety and depressive disorders. The preferredindications with regard to the present invention are the treatment ofanxiety and depressive disorders.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise stated, the following terms used in the presentdescription have the definitions given in the following. It must benoted that, as used in the specification and the appended claims, thesingular forms “a”, “an,” and “the” include plural forms unless thecontext clearly dictates otherwise.

In the present description, the term “alkyl,” alone or in combinationwith other groups, refers to a branched or straight-chain monovalentsaturated hydrocarbon radical. The term “C₁₋₆-alkyl” denotes a saturatedstraight- or branched-chain hydrocarbon group containing from 1 to 6carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, the isomeric pentyls and the like. A preferredsub-group of C₁₋₆-alkyl is C₁₋₄-alkyl, i.e. with 1-4 carbon atoms.

In the present invention, the term “alkylene” refers to a linear orbranched saturated divalent hydrocarbon radical. In particular,“C₁₋₆-alkylene”, means a linear saturated divalent hydrocarbon radicalof one to six carbon atoms or a branched saturated divalent hydrocarbonradical of three to six carbon atoms, e.g. methylene, ethylene,2,2-dimethylethylene, n-propylene, 2-methylpropylene, 1-methyl-ethylene,2-methyl-ethylene and the like.

In the present description, the terms “alkoxy” and “C₁₋₆-alkoxy” referto the group R′—O—, wherein R′ is alkyl or C₁₋₆-alkyl as defined above.Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, tert-butoxy, sec-butoxy and the like. A preferred sub-group ofC₁₋₆-alkoxy, and still more preferred alkoxy groups are methoxy and/orethoxy.

In the present description, the terms “thioalkyl” and “C₁₋₆-thioalkyl”refer to the group R′—S—, wherein R′ is alkyl or C₁₋₆-alkyl as definedabove. The term “—S(O)₀₋₂C₁₋₆-alkyl” hence refers to the residues—S—C₁₋₆-alkyl, —S(O)—C₁₋₆-alkyl, and —S(O)₂—C₁₋₆-alkyl whereinC₁₋₆-alkyl is as defined above.

The term “C₁₋₆-alkyl substituted by OH” is synonymous with“C₁₋₆-hydroxyalkyl” or “hydroxyl-C₁₋₆-alkyl” and means a C₁₋₆-alkylgroup as defined above wherein at least one of the hydrogen atoms of thealkyl group is replaced by a hydroxy group.

The term “C₁₋₆-alkyl substituted by CN” is synonymous with“C₁₋₆-cyanoalkyl” or “cyano-C₁₋₆-alkyl” and means a C₁₋₆-alkyl group asdefined above wherein at least one of the hydrogen atoms of the alkylgroup is replaced by a CN group.

The terms “halo” and “halogen” refer to fluorine (F), chlorine (Cl),bromine (Br) and iodine (I) with fluorine, chlorine and bromine beingpreferred.

The term “C₁₋₆-haloalkyl” is synonymous with “halo-C₁₋₆-alkyl” or“C₁₋₆-alkyl substituted by halo” and means a C₁₋₆-alkyl group as definedabove wherein at least one of the hydrogen atoms of the alkyl group isreplaced by a halogen atom, preferably fluoro or chloro, most preferablyfluoro. Examples of C₁₋₆-haloalkyl include but are not limited tomethyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl,pentyl or n-hexyl substituted by one or more Cl, F, Br or I atom(s) aswell as those groups specifically illustrated by the examples hereinbelow. Among the preferred C₁₋₆-haloalkyl groups are difluoro- ortrifluoro-methyl or -ethyl.

The term “C₁₋₆-haloalkoxy” is synonymous with “halo-C₁₋₆-alkoxy” or“C₁₋₆-alkoxy substituted by halo” and means a C₁₋₆-alkoxy group asdefined above wherein at least one of the hydrogen atoms of the alkylgroup is replaced by a halogen atom, preferably fluoro or chloro, mostpreferably fluoro. Among the preferred halogenated alkoxy groups aredifluoro- or trifluoro-methoxy or -ethoxy.

The term “C₂₋₁₂-alkenyl,” alone or in combination, denotes astraight-chain or branched hydrocarbon residue of 2 to 12 carbon atomscomprising at least one double bond. A preferred sub-group ofC₂₋₁₂-alkenyl is C₂₋₆-alkyenyl. Examples of the preferred alkenyl groupsare ethenyl, propen-1-yl, propen-2-yl(allyl), buten-1-yl, buten-2-yl,buten-3-yl, penten-1-yl, penten-2-yl, penten-3-yl, penten-4-yl,hexen-1-yl, hexen-2-yl, hexen-3-yl, hexen-4-yl and hexen-5-yl, as wellas those specifically illustrated by the examples herein below.

The term “5 or 6 membered heteroaryl” means a monovalent aromatic ringof 5 or 6 ring atoms as ring members containing one, two, three or fourring heteroatoms selected from N, O, and S, the rest being carbon atoms,whereby one, two or three heteroatoms are preferred, and one or twoheteroatoms are even more preferred. Examples of heteroaryl moietiesinclude, but are not limited to pyrrolyl, pyrazolyl, imidazolyl, furanyl(synonymous to furyl), thiophenyl (synonymous to thienyl), oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl. 5 or 6-membered heteroaryl are optionally substituted withone or more substituents. These optional substitutents include halo,C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl, C₁₋₆-cyanoalkyl,C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, —S(O)₀₋₂C₁₋₆-alkyl, nitro, hydroxy, cyano,—(C₁₋₆-alkylene)-O—C₁₋₆-alkyl, —(C₁₋₆-alkylene)-O—C₁₋₆-haloalkyl,—(C₁₋₆-alkylene)-OR′″, —C(O)OC₁₋₆-alkyl, —C(O)C₁₋₆-alkyl, —C(O)OR′″,—C(O)R′″, —C(O)NR′R″, —S(O)₂NR′R″, —(CH₂)_(x)—NR′R″,—(CH₂)_(x)—NR′C(O)—C₁₋₆-alkyl, —(CH₂)_(x)—NR′S(O)₂—C₁₋₆-alkyl,—(CH₂)_(x)—C₃₋₆-cycloalkyl, —(CH₂)_(x)—R′″, wherein x is from 0 to 4, R′and R″ are each independently H or C₁₋₆-alkyl, or R′ and R″ togetherwith the nitrogen to which they are bound form a 5 or 6-memberedheterocycle comprising one or two heteroatoms selected from N, O and S,and R′″ is phenyl or 5- to 6-membered heteroaryl, optionally substitutedwith one, two, or three halo, C₁₋₆-haloalkyl, C₁₋₆-alkyl, orC₁₋₆-alkoxy. Preferred substituents are halo, C₁₋₆-haloalkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, cyano, —CH₂CN, —CH₂OCH₃,—S(O)₂—C₁₋₆-alkyl, C₁₋₆-hydroxyalkyl, —NR′C(O)—C₁₋₄-alkyl,—C(O)N(C₁₋₄-alkyl)₂, —C(O)NH(C₁₋₄-alkyl), —S(O)₂N(C₁₋₄-alkyl)₂, or—S(O)₂NH(C₁₋₄-alkyl), or those substitutents as specifically indicatedherein.

The term “heterocycloalkyl” means a monovalent saturated ring,consisting of one ring of 3 to 7, preferably from 4 to 6 atoms as ringmembers, including one, two, three or four heteroatoms chosen fromnitrogen, oxygen or sulfur, the rest being carbon atoms, whereby one,two or three heteroatoms are preferred, and one or two heteroatoms areeven more preferred. It is understood that the number of heteroatomsdepends on the ring size, i.e. 3 and 4-membered heterocycloalkylpreferably contain one heteroatom, 5 to 7-membered heterocycloalkylpreferably contain one, two or three heteroatoms, and even morepreferably one or two heteroatoms. Examples of heterocyclic moietiesinclude, but are not limited to, oxiranyl, thiiranyl, aziridinyl,oxetanyl, azetidinyl, tetrahydro-furanyl, tetrahydro-thiophenyl(synonymous with tetrahydro-thienyl), pyrrolidinyl, pyrazolidinyl,imidazolidinyl, oxazidinyl, isoxazidinyl, thiazolidinyl,isothiazolidinyl, piperidinyl, piperazidinyl, morpholinyl, ortetrahydropyranyl, each of which is optionally substituted as describedherein. 3 to 7-membered heterocycloalkyl are optionally substituted withone or more substituents. These optional substitutents include halo,C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl, C₁₋₆-cyanoalkyl,C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, —S(O)₀₋₂C₁₋₆-alkyl, nitro, hydroxy, cyano,—(C₁₋₆-alkylene)-O—C₁₋₆-alkyl, —(C₁₋₆-alkylene)-O—C₁₋₆-haloalkyl,—(C₁₋₆-alkylene)-OR′″, —C(O)OC₁₋₆-alkyl, —C(O)C₁₋₆-alkyl, —C(O)OR′″,—C(O)R′″, —C(O)NR′R″, —S(O)₂NR′R″, —(CH₂)_(x)—NR′R″,—(CH₂)_(x)—NR′C(O)—C₁₋₆-alkyl, —(CH₂)_(x)—NR′S(O)₂—C₁₋₆-alkyl,—(CH₂)_(x)—C₃₋₆-cycloalkyl, —(CH₂)_(x)—R′″, wherein x is from 0 to 4, R′and R″ are each independently H or C₁₋₆-alkyl, or R′ and R″ togetherwith the nitrogen to which they are bound form a 5 or 6-memberedheterocycle comprising one or two heteroatoms selected from N, O and S,and R′″ is phenyl or 5- to 6-membered heteroaryl, optionally substitutedwith one, two, or three halo, C₁₋₆-haloalkyl, C₁₋₆-alkyl, orC₁₋₆-alkoxy. Preferred substituents are halo, C₁₋₆-haloalkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, cyano, —CH₂CN, —CH₂OCH₃,—S(O)₂—C₁₋₆-alkyl, C₁₋₆-hydroxyalkyl, —NR′C(O)—C₁₋₄-alkyl,—C(O)N(C₁₋₄-alkyl)₂, —C(O)NH(C₁₋₄-alkyl), —S(O)₂N(C₁₋₄-alkyl)₂, or—S(O)₂NH(C₁₋₄-alkyl), or those substitutents as specifically indicatedherein.

The term “one or more substituents” indicates that in principle everyposition in the aryl (in particular phenyl), heteroaryl,heterocycloalkyl and cycloalkyl residue may bear such a substituent. Thepentafluorophenyl residue may be mentioned as a preferred example.However, in 5 to 6-membered aromatic rings, one, two, or threesubstituents are preferred. In 5 to 6-membered saturated rings, one, twothree or four substituents are preferred. In 3 to 4-membered rings, oneor two substituents are preferred.

The term “heterocycle” in the definition “R′ and R″, together with thenitrogen to which they are bound form a five- or six-memberedheterocycle comprising one or two heteroatoms selected from the group ofnitrogen, oxygen and sulfur” means either heterocycloalkyl or partiallyunsaturated heterocycloalkyl (synonymous with heterocycloalkenyl), whichmay optionally be substituted with one, two or three substituentsselected from halo, C₁₋₆-haloalkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-haloalkoxy, nitro, and cyano. Preferred heterocycles arepiperazine, N-methylpiperazine, morpholin, piperidine and pyrrolidine.

The term “C₃₋₇-cycloalkyl” denotes a monovalent or divalent saturatedcarbocyclic moiety consisting of a monocyclic ring containing from 3 to7 ring carbon atoms. Cycloalkyl can optionally be substituted with one,two, three or four substituents, wherein each substituent isindependently hydroxy, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, amino, unlessotherwise specifically indicated. Examples of cycloalkyl moietiesinclude optionally substituted cyclopropyl, optionally substitutedcyclobutyl, optionally substituted cyclopentyl and optionallysubstituted cyclohexyl as well as those specifically illustrated by theexamples herein below.

“Pharmaceutically acceptable,” such as pharmaceutically acceptablecarrier, excipient, etc., means pharmacologically acceptable andsubstantially non-toxic to the subject to which the particular compoundis administered.

The term “pharmaceutically acceptable acid addition salt” or“pharmaceutically acceptable salt” embraces salts with inorganic andorganic acids, such as hydrochloric acid, nitric acid, sulfuric acid,phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid,acetic acid, succinic acid, tartaric acid, methane-sulfonic acid,p-toluenesulfonic acid and the like.

“Therapeutically effective amount” means an amount that is effective toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

The invention further comprises individual optical isomers of thecompounds described herein as well as racemic and non-racemic mixturesthereof.

In detail, the present invention relates to compounds of the generalformula (I)

wherein

-   X is CH₂, and Y is C═O,-   X is O, and Y is C═O, or-   X—Y is N═N;-   R¹ is H,    -   C₁₋₁₂-alkyl, optionally substituted with CN or OH,    -   C₁₋₆-haloalkyl,    -   C₂₋₁₂-alkenyl,    -   —(CR^(i)R^(ii))_(m)—R^(a),        -   wherein R^(i) and R^(ii) are independently from each other            H, methyl, or ethyl;        -   wherein m is from 0 to 4;        -   wherein R^(a) is            -   phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered                heterocycloalkyl                -   or 3 to 7-membered cycloalkyl,                -    which are optionally substituted with one or more                    A, or            -   —NR^(b)R^(c), wherein R^(b) and R^(c) are each                independently                -   hydrogen,                -   hydroxy,                -   C₁₋₆-alkyl,                -   —S(O)₂—C₁₋₆-alkyl, or                -   —C(O)—C₁₋₆-alkyl,    -   —(CR^(iii)R^(iv))_(n)—C(O)R^(d),        -   wherein R^(iii) and R^(iv) are independently from each other            H, methyl, or ethyl;        -   wherein n is from 0 to 4;        -   wherein R^(d) is            -   C₁₋₆-alkoxy,            -   —NR^(e)R^(f), wherein R^(e) and R^(f) are each                independently                -   hydrogen,                -   C₁₋₆-alkyl, or                -   —(C₂₋₆-alkylene)NR^(g)R^(h); wherein R^(g) and R^(h)                    are each independently                -    hydrogen, C₁₋₆-alkyl, or —C(O)O—C₁₋₆-alkyl, or            -   phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered                heterocycloalkyl                -   or 3 to 7-membered cycloalkyl,                -    which are optionally substituted with one or more                    A,    -   —S(O)₂-phenyl, wherein phenyl is optionally substituted with one        or more halo, C₁₋₆-haloalkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,        C₁₋₆-haloalkoxy, nitro, hydroxy or cyano;    -   —S(O)₂—C₁₋₆-alkyl,    -   —S(O)₂N(C₁₋₆-alkyl)₂, or    -   —S(O)₂NH(C₁₋₆-alkyl);-   A is halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl,    C₁₋₆-cyanoalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, —S(O)₀₋₂C₁₋₆-alkyl,    nitro, hydroxy, cyano,    -   —(C₁₋₆-alkylene)-O—C₁₋₆-alkyl,        —(C₁₋₆-alkylene)-O—C₁₋₆-haloalkyl, —(C₁₋₆-alkylene)-OR′″,        —C(O)OC₁₋₆-alkyl, —C(O)C₁₋₆-alkyl, —C(O)OR′″, —C(O)R′″,        —C(O)NR′R″, —S(O)₂NR′R″, —(CH₂)_(x)—NR′R″,        —(CH₂)_(x)—NR′C(O)—C₁₋₆-alkyl, —(CH₂)_(x)—NR′S(O)₂—C₁₋₆-alkyl,        —(CH₂)_(x)—C₃₋₆-cycloalkyl, or —(CH₂)_(x)—R′″,        -   wherein x is from 0 to 4,        -   R′ and R″ are each independently H or C₁₋₆-alkyl, or        -   R′ and R″ together with the nitrogen to which they are bound            form a 5 or 6-membered heterocycle comprising one or two            heteroatoms selected from N, O and S, and        -   R′″ is phenyl or 5- to 6-membered heteroaryl, optionally            substituted with one, two, or three halo, C₁₋₆-haloalkyl,            C₁₋₆-alkyl, or C₁₋₆-alkoxy,-   R² is hydrogen,    -   C₁₋₆-alkyl, or    -   —C(O)R^(n), wherein R^(n) is        -   C₁₋₆-alkyl, or        -   3 to 7-membered heterocycloalkyl, optionally substituted            with one, two or three C₁₋₆-alkyl, —C(O)O—C₁₋₆-alkyl, or            —S(O)₂—C₁₋₆-alkyl,        -   NR^(j)R^(k), wherein R^(j) and R^(k) are each independently            -   hydrogen,            -   C₁₋₆-alkyl, or            -   —(C₂₋₆-alkylene)-NR^(l)R^(m); wherein R^(l) and R^(m)                are each independently hydrogen, C₁₋₆-alkyl, or                —C(O)O—C₁₋₆-alkyl; or-   R¹ together with R² forms a 5- to 6-membered heterocycloalkyl moiety    fused to the indole core, bearing one or two ring heteroatoms    selected from N, S and O, and being optionally substituted by one or    more A;-   R³, R⁴, R⁵, R⁶ are each independently hydrogen, halo, C₁₋₆-alkyl,    halo-C₁₋₆-alkyl, C₁₋₆-alkoxy or C₁₋₆-haloalkoxy;-   R⁷, R⁸, R⁹, R¹⁰ are each independently hydrogen, halo, C₁₋₆-alkyl,    halo-C₁₋₆-alkyl, C₁₋₆-alkoxy or C₁₋₆-haloalkoxy;-   or a pharmaceutically acceptable salt thereof,-   with the proviso that compounds wherein R¹, R², R³, R⁴, R⁵ and R⁶    are all simultaneously hydrogen are excluded.

In the following, certain embodiments of the invention are disclosed,whereby the combination of these embodiments with each other is alsoencompassed by present invention.

In certain embodiments of the invention, R¹ is hydrogen. However, notall residues R¹ to R⁶ shall simultaneously be hydrogen.

In certain embodiments of the invention, R¹ is C₁₋₁₂-alkyl, optionallysubstituted with CN or OH; or R¹ is C₂₋₁₂-alkyl, optionally substitutedwith CN or OH. Preferably, R¹ is C₁₋₆-alkyl, optionally substituted withCN or OH; or R¹ is C₂₋₆-alkyl, optionally substituted with CN or OH.

In certain embodiments of the invention, R¹ is C₁₋₆-haloalkyl orC₂₋₁₂-alkenyl. In case R¹ is alkenyl, C₂₋₆-alkenyl is preferred.

In certain embodiments of the invention,

-   R¹ is —(CR^(i)R^(ii))_(m)—R^(a),    -   wherein R^(i) and R^(ii) are independently from each other H,        methyl, or ethyl;    -   wherein m is from 0 to 4;    -   wherein R^(a) is        -   phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered            heterocycloalkyl            -   or 3 to 7-membered cycloalkyl,                -   which are optionally substituted with one or more                    halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl,                    C₁₋₆-cyanoalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy,                    —S(O)₀₋₂C₁₋₆-alkyl, nitro, hydroxy, cyano,                    —(C₁₋₆-alkylene)-O—C₁₋₆-alkyl,                    —(C₁₋₆-alkylene)-O—C₁₋₆-haloalkyl,                    —(C₁₋₆-alkylene)-OR′″, —C(O)OC₁₋₆-alkyl,                    —C(O)C₁₋₆-alkyl, —C(O)OR′″, —C(O)R′″, —C(O)NR′R″,                    —S(O)₂NR′R″, —(CH₂)_(x)—NR′R″,                    —(CH₂)_(x)—NR′C(O)—C₁₋₆-alkyl,                    —(CH₂)_(x)—NR′S(O)₂—C₁₋₆-alkyl,                    —(CH₂)_(x)—C₃₋₆-cycloalkyl, or —(CH₂)_(x)—R′″,                -    wherein x is from 0 to 4,                -    R′ and R″ are each independently H or C₁₋₆-alkyl,                    or                -    R′ and R″ together with the nitrogen to which they                    are bound form a 5 or 6-membered heterocycle                    comprising one or two heteroatoms selected from N, O                    and S, and                -    R′″ is phenyl or 5- to 6-membered heteroaryl,                    optionally substituted with one, two, or three halo,                    C₁₋₆-haloalkyl, C₁₋₆-alkyl, or C₁₋₆-alkoxy,        -   —NR^(b)R^(c), wherein R^(b) and R^(c) are each independently            -   hydrogen,            -   hydroxy,            -   C₁₋₆-alkyl,            -   —S(O)₂—C₁₋₆-alkyl, or            -   —C(O)—C₁₋₆-alkyl.-   In —(CR^(i)R^(ii))_(m)—R^(a), preferably, all R^(i) and R^(ii) are    hydrogen, or one R^(i) is methyl and the other R^(i) and R^(ii) are    hydrogen. The following linkers —(CR^(i)R^(ii))_(m)— are preferred:    —CH₂—, —CH(CH₃)—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)CH₂—, —CH₂CH(CH₃)—,    —CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)CH₂—, or —CH₂CH₂CH(CH₃)—.

The variable m in —(CR^(i)R^(ii))_(m)—R^(a) is 0, 1, 2, 3 or 4. In caseR^(a) is —NR^(b)R^(c), m is preferably 1, 2, 3 or 4.

When R^(a) in —(CR^(i)R^(ii))_(m)—R^(a) is 5 to 6-membered heteroaryl,then 5- to 6-membered heteroaryl is as defined above, namely pyrrolyl,pyrazolyl, imidazolyl, furanyl (synonymous to furyl), thiophenyl(synonymous to thienyl), oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl. In case m is 0,pyridinyl is preferred, in case m is 1, 2, 3 or 4, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, or thiazolyl are preferred. All these residues areoptionally substituted as described herein.

When R^(a) in —(CR^(i)R^(ii))_(m)—R^(a) is a 3- to 7-memberedheterocycloalkyl, then 3- to 7-membered heterocycloalkyl is as definedabove, namely oxiranyl, thiiranyl, aziridinyl, oxetanyl, azetidinyl,tetrahydro-furanyl, tetrahydro-thiophenyl (synonymous withtetrahydro-thienyl), pyrrolidinyl, pyrazolidinyl, imidazolidinyl,oxazidinyl, isoxazidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl,piperazidinyl, morpholinyl, or tetrahydropyranyl. When R^(a) is 3- to7-membered heterocycloalkyl, oxiranyl, oxetanyl, pyrrolidinyl,piperidinyl, piperazidinyl, morpholinyl, or tetrahydropyranyl arepreferred. All these residues are optionally substituted as describedherein.

When R′″ is 5 to 6-membered heteroaryl, then 5- to 6-membered heteroarylis as defined above, namely pyrrolyl, pyrazolyl, imidazolyl, furanyl(synonymous to furyl), thiophenyl (synonymous to thienyl), oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl. Pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, or thiazolyl are preferred.

In certain embodiments of the invention,

-   R¹ is —(CR^(iii)R^(iv))_(n)—C(O)R^(d),    -   wherein R^(iii) and R^(iv) are independently from each other H,        methyl, or ethyl;    -   wherein n is from 0 to 4;    -   wherein R^(d) is        -   C₁₋₆-alkoxy,        -   —NR^(e)R^(f), wherein R^(e) and R^(f) are each independently            -   hydrogen,            -   C₁₋₆-alkyl, or            -   —(C₂₋₆-alkylene)NR^(g)R^(h); wherein R^(g) and R^(h) are                each independently                -   hydrogen, C₁₋₆-alkyl, or —C(O)O—C₁₋₆-alkyl, or        -   phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered            heterocycloalkyl            -   or 3 to 7-membered cycloalkyl,                -   which are optionally substituted with one or more                    halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl,                    C₁₋₆-cyanoalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy,                    —S(O)₀₋₂C₁₋₆-alkyl, nitro, hydroxy, cyano,                    —(C₁₋₆-alkylene)-O—C₁₋₆-alkyl,                    —(C₁₋₆-alkylene)-O—C₁₋₆-haloalkyl,                    —(C₁₋₆-alkylene)-OR′″, —C(O)OC₁₋₆-alkyl,                    —C(O)C₁₋₆-alkyl, —C(O)OR′″, —C(O)R′″, —C(O)NR′R″,                    —S(O)₂NR′R″, —(CH₂)_(x)—NR′R″,                    —(CH₂)_(x)—NR′C(O)—C₁₋₆-alkyl,                    —(CH₂)_(x)—NR′S(O)₂—C₁₋₆-alkyl,                    —(CH₂)_(x)—C₃₋₆-cycloalkyl, or —(CH₂)_(x)—R′″,                -    wherein x is from 0 to 4,                -    R′ and R″ are each independently H or C₁₋₆-alkyl,                    or                -    R′ and R″ together with the nitrogen to which they                    are bound form a 5 or 6-membered heterocycle                    comprising one or two heteroatoms selected from N, O                    and S, and                -    R′″ is phenyl or 5- to 6-membered heteroaryl,                    optionally substituted with one, two, or three halo,                    C₁₋₆-haloalkyl, C₁₋₆-alkyl, or C₁₋₆-alkoxy.

In —(CR^(iii)R^(iv))_(n)—C(O)R^(d), preferably, all R^(iii) and R^(iv)are hydrogen, or one R^(iii) is methyl and the other R^(iii) and R^(iv)are hydrogen. The following linkers —(CR^(i)R^(ii))_(n)— are preferred:—CH₂—, —CH(CH₃)—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)CH₂—, —CH₂CH(CH₃)—,—CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)CH₂—, or —CH₂CH₂CH(CH₃)—.

The variable n in —(CR^(iii)R^(iv))_(n)—C(O)R^(d) is 0, 1, 2, 3 or 4.

When R^(d) in —(CR^(iii)R^(iv))_(n)—C(O)R^(d) is 5 to 6-memberedheteroaryl, then 5- to 6-membered heteroaryl is as defined above, namelypyrrolyl, pyrazolyl, imidazolyl, furanyl (synonymous to furyl),thiophenyl (synonymous to thienyl), oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl. When R^(d)is 5- to 6-membered heteroaryl, optionally substituted pyridinyl ispreferred. All these residues are optionally substituted as describedherein.

When R^(d) in —(CR^(iii)R^(iv))_(n)—C(O)R^(d) is a 3- to 7-memberedheterocycloalkyl, then 3- to 7-membered heterocycloalkyl is as definedabove, namely oxiranyl, thiiranyl, aziridinyl, oxetanyl, azetidinyl,tetrahydro-furanyl, tetrahydro-thiophenyl (synonymous withtetrahydro-thienyl), pyrrolidinyl, pyrazolidinyl, imidazolidinyl,oxazidinyl, isoxazidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl,piperazidinyl, morpholinyl, or tetrahydropyranyl. When R^(d) is 3- to7-membered heterocycloalkyl, optionally substituted piperidinyl,piperazidinyl, or morpholinyl are preferred. All these residues areoptionally substituted as described herein.

When R′″ is 5 to 6-membered heteroaryl, then 5- to 6-membered heteroarylis as defined above, namely pyrrolyl, pyrazolyl, imidazolyl, furanyl(synonymous to furyl), thiophenyl (synonymous to thienyl), oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl. Pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, or thiazolyl are preferred.

In certain embodiments of the invention, R¹ is —S(O)₂-phenyl, whereinphenyl is optionally substituted with one or more halo, C₁₋₆-haloalkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, nitro, hydroxy or cyano. Halo,CF₃, C₁₋₄-alkyl, C₁₋₆-alkoxy, OCF₃ and cyano are preferredsubstitutents.

In certain embodiments of the invention, R¹ is —S(O)₂—C₁₋₆-alkyl,—S(O)₂N(C₁₋₆-alkyl)₂, or —S(O)₂NH(C₁₋₆-alkyl).

It is understood that all the above residues R¹ are encompassed bypresent invention in all their possible combinations. Some examples aregiven below.

In certain embodiments of the invention,

-   A is halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl,    C₁₋₆-cyanoalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, —S(O)₀₋₂C₁₋₆-alkyl,    nitro, cyano, —(C₁₋₆-alkylene)-O—C₁₋₆-alkyl, —(C₁₋₆-alkylene)-OR′″,    —C(O)OC₁₋₆-alkyl, —C(O)NR′R″, —S(O)₂NR′R″, —(CH₂)_(x)—NR′R″,    —(CH₂)_(x)—NR′C(O)—C₁₋₆-alkyl, —(CH₂)_(x)—NR′S(O)₂—C₁₋₆-alkyl,    —(CH₂)_(x)—C₃₋₆-cycloalkyl, or —(CH₂)_(x)—R′″,    -   wherein x is from 0 to 4,    -   R′ and R″ are each independently H or C₁₋₆-alkyl, or    -   R′ and R″ together with the nitrogen to which they are bound        form a 5 or 6-membered heterocycle comprising one or two        heteroatoms selected from N, O and S, and    -   R′″ is phenyl, optionally substituted with one, two, or three        halo, C₁₋₆-haloalkyl, C₁₋₆-alkyl, or C₁₋₆-alkoxy.

In certain embodiments of formula (I) of the invention,

-   A is halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl,    C₁₋₆-cyanoalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, C₁₋₆-thioalkyl,    —S(O)₂—C₁₋₆-alkyl, cyano, —CH₂OCH₃, —C(O)O—C₁₋₆-alkyl, —C(O)NR′R″,    —S(O)₂NR′R″, —NR′C(O)—C₁₋₆-alkyl, —NR′S(O)₂—C₁₋₆-alkyl, benzyl, or    phenyl    -   wherein R′ and R″ are each independently H or C₁₋₆-alkyl.

In certain embodiments of formula (I) of the invention,

-   R¹ is H,    -   C₂₋₆-alkyl, optionally substituted with CN or OH,    -   C₁₋₆-haloalkyl,    -   —(CR^(i)R^(ii))_(m)—R^(a),        -   wherein R^(i) and R^(ii) are independently from each other            H, methyl, or ethyl;        -   wherein m is from 0 to 4;        -   wherein R^(a) is            -   phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered                heterocycloalkyl                -   or 3 to 7-membered cycloalkyl,                -    which are optionally substituted with one or more                    A, or            -   —NR^(b)R^(c), wherein R^(b) and R^(c) are each                independently                -   hydrogen, C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, or                    —C(O)—C₁₋₆-alkyl,    -   —(CR^(iii)R^(iv))_(n)—C(O)R^(d),        -   wherein R^(iii) and R^(iv) are independently from each other            H, methyl, or ethyl;        -   wherein n is from 0 to 4;        -   wherein R^(d) is            -   C₁₋₆-alkoxy,            -   —NR^(e)R^(f), wherein R^(e) and R^(f) are each                independently                -   hydrogen,                -   C₁₋₆-alkyl, or                -   —(C₂₋₆-alkylene)NR^(g)R^(h); wherein R^(g) and R^(h)                    are each independently                -    hydrogen, C₁₋₆-alkyl, or —C(O)O—C₁₋₆-alkyl, or            -   phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered                heterocycloalkyl                -   or 3 to 7-membered cycloalkyl,                -    which are optionally substituted with one or more                    A,    -   —S(O)₂—C₁₋₆-alkyl,    -   —S(O)₂N(C₁₋₆-alkyl)₂, or    -   —S(O)₂NH(C₁₋₆-alkyl);-   A is halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl,    C₁₋₆-cyanoalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, —S(O)₀₋₂C₁₋₆-alkyl,    nitro, hydroxy, cyano, —(C₁₋₆-alkylene)-O—C₁₋₆-alkyl,    —(C₁₋₆-alkylene)-O—C₁₋₆-haloalkyl, —(C₁₋₆-alkylene)-OR′″,    —C(O)OC₁₋₆-alkyl, —C(O)C₁₋₆-alkyl, —C(O)OR′″, —C(O)R′″, —C(O)NR′R″,    —S(O)₂NR′R″, —(CH₂)_(x)—NR′R″, —(CH₂)_(x)—NR′C(O)—C₁₋₆-alkyl,    —(CH₂)_(x)—NR′S(O)₂—C₁₋₆-alkyl, —(CH₂)_(x)—C₃₋₆-cycloalkyl, or    —(CH₂)_(x)—R′″,    -   wherein x is from 0 to 4,    -   R′ and R″ are each independently H or C₁₋₆-alkyl, or    -   R′ and R″ together with the nitrogen to which they are bound        form a 5 or 6-membered heterocycle comprising one or two        heteroatoms selected from N, O and S, and    -   R′″ is phenyl or 5- to 6-membered heteroaryl, optionally        substituted with one, two, or three halo, C₁₋₆-haloalkyl,        C₁₋₆-alkyl, or C₁₋₆-alkoxy.

In certain embodiments of formula (I) of the invention,

-   R¹ is H,    -   C₂₋₆-alkyl, optionally substituted with CN or OH,    -   C₁₋₆-haloalkyl,    -   (CR^(i)R^(ii))_(m)—R^(a),        -   wherein R^(i) and R^(ii) are independently from each other            H, methyl, or ethyl;        -   wherein m is from 1 to 4;        -   wherein R^(a) is            -   phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered                heterocycloalkyl                -   or 3 to 7-membered cycloalkyl,                -    which are optionally substituted with one or more                    A, or            -   —NR^(b)R^(c), wherein R^(b) and R^(c) are each                independently                -   hydrogen, C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, or                    —C(O)—C₁₋₆-alkyl,    -   —(CR^(iii)R^(iv))_(n)—C(O)R^(d),        -   wherein R^(iii) and R^(iv) are independently from each other            H, methyl, or ethyl;        -   wherein n is from 0 to 4;        -   wherein R^(d) is            -   C₁₋₆-alkoxy,            -   —NR^(e)R^(f), wherein R^(e) and R^(f) are each                independently                -   hydrogen,                -   C₁₋₆-alkyl, or                -   —(C₂₋₆-alkylene)NR^(g)R^(h); wherein R^(g) and R^(h)                    are each independently                -    hydrogen, C₁₋₆-alkyl, or —C(O)O—C₁₋₆-alkyl, or            -   phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered                heterocycloalkyl                -   or 3 to 7-membered cycloalkyl,                -    which are optionally substituted with one or more                    A,    -   —S(O)₂—C₁₋₆-alkyl,    -   —S(O)₂N(C₁₋₆-alkyl)₂, or    -   —S(O)₂NH(C₁₋₆-alkyl);-   A is halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl,    C₁₋₆-cyanoalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, —S(O)₀₋₂C₁₋₆-alkyl,    nitro, cyano, —(C₁₋₆-alkylene)-O—C₁₋₆-alkyl, —(C₁₋₆-alkylene)-OR′″,    —C(O)OC₁₋₆-alkyl, —C(O)NR′R″, —S(O)₂NR′R″, —(CH₂)_(x)—NR′R″,    —(CH₂)_(x)—NR′C(O)—C₁₋₆-alkyl, —(CH₂)_(x)—NR′S(O)₂—C₁₋₆-alkyl,    —(CH₂)_(x)—C₃₋₆-cycloalkyl, or —(CH₂)_(x)—R′″,    -   wherein x is from 0 to 4,    -   R′ and R″ are each independently H or C₁₋₆-alkyl, or    -   R′ and R″ together with the nitrogen to which they are bound        form a 5 or 6-membered heterocycle comprising one or two        heteroatoms selected from N, O and S, and    -   R′″ is phenyl, optionally substituted with one, two, or three        halo, C₁₋₆-haloalkyl, C₁₋₆-alkyl, or C₁₋₆-alkoxy.-   Preferably, A is selected from    -   halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl,        C₁₋₆-cyanoalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, C₁₋₆-thioalkyl,        —S(O)₂—C₁₋₆-alkyl, cyano, —CH₂OCH₃, —C(O)O—C₁₋₆-alkyl,        —C(O)NR′R″, —S(O)₂NR′R″, —NR′C(O)—C₁₋₆-alkyl,        —NR′S(O)₂—C₁₋₆-alkyl, benzyl, and phenyl        -   wherein R′ and R″ are each independently H or C₁₋₆-alkyl.

In certain embodiments of formula (I) of the invention, R¹ together withR² forms a 5- to 6-membered heterocycloalkyl moiety fused to the indolecore, bearing one or two ring heteroatoms selected from N, S and O, andbeing optionally substituted by one or more A. Thereby, A is as definedabove. Preferably, the optional substituents are selected fromC₁₋₆-alkyl, halo, C₁₋₆-haloalkyl, C₁₋₆-alkoxy and C₁₋₆-haloalkoxy.Preferably, it is one optional substituent.

In certain embodiments of formula (I) of the invention,

-   R¹ is H,    -   —(CR^(i)R^(ii))_(m)—R^(a),        -   wherein R^(i) and R^(ii) are H, and m is 1 or 2;        -   wherein R^(a) is            -   phenyl, optionally substituted with one or more A,                preferably with halo,            -   —NR^(b)R^(c), wherein R^(b) and R^(c) are each                independently                -   hydrogen, C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, or                    —C(O)—C₁₋₆-alkyl, or    -   —(CR^(iii)R^(iv))_(n)—C(O)R^(d),        -   wherein R^(iii) and R^(iv) are H, and n is 1, and R^(d) is            -   —NR^(e)R^(f), wherein R^(e) and R^(f) are each                independently hydrogen or C₁₋₆-alkyl,-   or-   R¹ together with R² forms a 6-membered hetercycloalkyl moiety fused    to the indole core, bearing two nitrogen ring heteroatoms, and being    optionally substituted by one or more C₁₋₆-alkyl, halo,    C₁₋₆-haloalkyl, C₁₋₆-alkoxy or C₁₋₆-haloalkoxy,-   A is halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl,    C₁₋₆-cyanoalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, C₁₋₆-thioalkyl,    —S(O)₂—C₁₋₆-alkyl, cyano, —CH₂OCH₃, —C(O)O—C₁₋₆-alkyl, —C(O)NR′R″,    —S(O)₂NR′R″, —NR′C(O)—C₁₋₆-alkyl, —NR′S(O)₂—C₁₋₆-alkyl, benzyl, or    phenyl    -   wherein R′ and R″ are each independently H or C₁₋₆-alkyl.

When R^(n) in —C(O)R^(n) of R² is a 3- to 7-membered heterocycloalkyl,then 3- to 7-membered heterocycloalkyl is as defined above, namelyoxiranyl, thiiranyl, aziridinyl, oxetanyl, azetidinyl,tetrahydro-furanyl, tetrahydro-thiophenyl (synonymous withtetrahydro-thienyl), pyrrolidinyl, pyrazolidinyl, imidazolidinyl,oxazidinyl, isoxazidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl,piperazidinyl, morpholinyl, or tetrahydropyranyl. When R^(n) is 3- to7-membered heterocycloalkyl, piperidinyl, piperazidinyl, or morpholinyl,optionally substituted with one methyl, are preferred.

In certain embodiments of the invention, R² of the compounds of formula(I) is hydrogen or C₁₋₆-alkyl.

In certain embodiments of the invention, R¹ together with R² of formula(I) forms a 5- to 6-membered heterocycloalkyl moiety fused to the indolecore, bearing one or two ring heteroatoms selected from N, S and O, andbeing optionally substituted by one or more A. Preferably, the optionalsubstituents are C₁₋₆-alkyl, halo, C₁₋₆-haloalkyl, C₁₋₆-alkoxy orC₁₋₆-haloalkoxy. Preferably, R¹ together with R² of formula (I) forms a6-membered hetercycloalkyl moiety fused to the indole core, bearing twonitrogen ring heteroatoms, and being optionally substituted by one ormore C₁₋₆-alkyl, halo, C₁₋₆-haloalkyl, C₁₋₆-alkoxy or C₁₋₆-haloalkoxy.

In certain embodiments of the invention, R³, R⁴, R⁵, R⁶ are eachindependently hydrogen, halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy orC₁₋₆-haloalkoxy.

In certain embodiments of the invention, R³ and R⁶ of formula (I) arehydrogen.

In certain embodiments of the invention, R⁴ of formula (I) is hydrogen,Cl, F or methyl.

In certain embodiments of the invention, R⁵ of formula (I) is hydrogen,halo, CF₃, methoxy or —OCF₃. If R⁵ is hydrogen, R¹ is preferably asdefined above, however, with the exclusion of hydrogen. In furtherembodiments, R⁵ is halo, CF₃, methoxy or —OCF₃. In further embodiments,R⁵ is Cl, F or methoxy; in further embodiments, R⁵ is Cl.

In certain embodiments of the invention, R³ and R⁶ are hydrogen, R⁴ ishydrogen, F, Cl or methyl, and R⁵ is halo, CF₃, methoxy or OCF₃.

In certain embodiments of the invention, R⁷, R⁸, R⁹, R¹⁰ are eachindependently hydrogen, halo, C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁₋₆-alkoxyor C₁₋₆-haloalkoxy. Preferably, R⁷, R⁸, R⁹, R¹⁰ are each hydrogen.

In a certain embodiment the compounds of the invention are thosecompounds of formula (I-a):

In a certain embodiment the compounds of the invention are thosecompounds of formula (I-b):

In a certain embodiment the compounds of the invention are thosecompounds of formula (I-c):

One embodiment of the invention encompasses compounds of formula (I)

wherein

-   X is CH₂, and Y is C═O,-   X is O, and Y is C═O, or-   X—Y is N═N;-   R¹ is H,    -   C₁₋₁₂-alkyl, optionally substituted with CN or OH,    -   C₁₋₆-haloalkyl,    -   C₂₋₁₂-alkenyl,    -   —(CR^(i)R^(ii))_(m)—R^(a),        -   wherein R^(i) and R^(ii) are independently from each other            H, methyl, or ethyl;        -   wherein m is from 0 to 4;        -   wherein R^(a) is            -   phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered                heterocycloalkyl                -   or 3 to 7-membered cycloalkyl,                -    which are optionally substituted with one or more                    A, or            -   —NR^(b)R^(c), wherein R^(b) and R^(c) are each                independently                -   hydrogen,                -   hydroxy,                -   C₁₋₆-alkyl,                -   —S(O)₂—C₁₋₆-alkyl, or                -   —C(O)—C₁₋₆-alkyl,    -   —(CR^(iii)R^(iv))_(n)—C(O)R^(d),        -   wherein R^(iii) and R^(iv) are independently from each other            H, methyl, or ethyl;        -   wherein n is from 0 to 4;        -   wherein R^(d) is            -   C₁₋₆-alkoxy,            -   —NR^(e)R^(f), wherein R^(e) and R^(f) are each                independently                -   hydrogen,                -   C₁₋₆-alkyl, or                -   —(C₂₋₆-alkylene)-NR^(g)R^(h); wherein R^(g) and                    R^(h) are each independently                -    hydrogen, C₁₋₆-alkyl, or —C(O)O—C₁₋₆-alkyl, or            -   phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered                heterocycloalkyl                -   or 3 to 7-membered cycloalkyl,                -    which are optionally substituted with one or more                    A,    -   —S(O)₂-phenyl, wherein phenyl is optionally substituted with one        or more halo, C₁₋₆-haloalkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,        C₁₋₆-haloalkoxy, nitro, hydroxy or cyano;    -   —S(O)₂—C₁₋₆-alkyl,    -   —S(O)₂N(C₁₋₆-alkyl)₂, or    -   —S(O)₂NH(C₁₋₆-alkyl);-   A is halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl,    C₁₋₆-cyanoalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, —S(O)₀₋₂C₁₋₆-alkyl,    nitro, hydroxy, cyano, —(C₁₋₆-alkylene)-O—C₁₋₆-alkyl,    —(C₁₋₆-alkylene)-O—C₁₋₆-haloalkyl, —(C₁₋₆-alkylene)-OR′″,    —C(O)OC₁₋₆-alkyl, —C(O)C₁₋₆-alkyl, —C(O)OR′″, —C(O)R′″, —C(O)NR′R″,    —S(O)₂NR′R″, —(CH₂)_(x)—NR′R″, —(CH₂)_(x)—NR′C(O)—C₁₋₆-alkyl,    —(CH₂)_(x)—NR′S(O)₂—C₁₋₆-alkyl, —(CH₂)_(x)—C₃₋₆-cycloalkyl, or    —(CH₂)_(x)—R′″,    -   wherein x is from 0 to 4,    -   R′ and R″ are each independently H or C₁₋₆-alkyl, or    -   R′ and R″ together with the nitrogen to which they are bound        form a 5 or 6-membered heterocycle comprising one or two        heteroatoms selected from N, O and S, and    -   R′″ is phenyl or 5- to 6-membered heteroaryl, optionally        substituted with one, two, or three halo, C₁₋₆-haloalkyl,        C₁₋₆-alkyl, or C₁₋₆-alkoxy,-   R² is hydrogen,    -   C₁₋₆-alkyl, or    -   —C(O)R^(n), wherein R^(n) is        -   C₁₋₆-alkyl,        -   3 to 7-membered heterocycloalkyl, optionally substituted            with one, two or three C₁₋₆-alkyl, —C(O)O—C₁₋₆-alkyl, or            —S(O)₂—C₁₋₆-alkyl, or        -   NR^(j)R^(k), wherein R^(j) and R^(k) are each independently            -   hydrogen,            -   C₁₋₆-alkyl, or            -   —(C₂₋₆-alkylene)-NR^(l)R^(m); wherein R^(l) and R^(m)                are each independently hydrogen, C₁₋₆-alkyl, or                —C(O)O—C₁₋₆-alkyl;-   R³, R⁴, R⁵, R⁶ are each independently hydrogen, halo, C₁₋₆-alkyl,    halo-C₁₋₆-alkyl, C₁₋₆-alkoxy or C₁₋₆-haloalkoxy;-   R⁷, R⁸, R⁹, R¹⁰ are each independently hydrogen, halo, C₁₋₆-alkyl,    halo-C₁₋₆-alkyl, C₁₋₆-alkoxy or C₁₋₆-haloalkoxy;-   or a pharmaceutically acceptable salt thereof,-   with the proviso that compounds wherein R¹, R², R³, R⁴, R⁵ and R⁶    are all simultaneously hydrogen are excluded.

The invention further encompasses an embodiment of formula (I) wherein

-   -   X is CH₂, and Y is C═O,    -   X is O, and Y is C═O, or    -   X—Y is N═N;

-   R¹ is H,    -   C₂₋₆-alkyl, optionally substituted with CN or OH,    -   C₁₋₆-haloalkyl,    -   —(CR^(i)R^(ii))_(m)—R^(a),        -   wherein R^(i) and R^(ii) are independently from each other            H, methyl, or ethyl;        -   wherein m is from 0 to 4;        -   wherein R^(a) is            -   phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered                heterocycloalkyl                -   or 3 to 7-membered cycloalkyl,                -    which are optionally substituted with one or more                    A, or            -   —NR^(b)R^(c), wherein R^(b) and R^(c) are each                independently                -   hydrogen, C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, or                    —C(O)—C₁₋₆-alkyl,    -   —(CR^(iii)R^(iv))_(n)—C(O)R^(d),        -   wherein R^(iii) and R^(iv) are independently from each other            H, methyl, or ethyl;        -   wherein n is from 0 to 4;        -   wherein R^(d) is            -   C₁₋₆-alkoxy,            -   —NR^(e)R^(f), wherein R^(e) and R^(f) are each                independently                -   hydrogen,                -   C₁₋₆-alkyl, or                -   —(C₂₋₆-alkylene)NR^(g)R^(h); wherein R^(g) and R^(h)                    are each independently                -    hydrogen, C₁₋₆-alkyl, or —C(O)O—C₁₋₆-alkyl, or            -   phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered                heterocycloalkyl                -   or 3 to 7-membered cycloalkyl,                -    which are optionally substituted with one or more                    A,    -   —S(O)₂-phenyl, optionally substituted by halo,    -   —S(O)₂—C₁₋₆-alkyl,    -   —S(O)₂N(C₁₋₆-alkyl)₂, or    -   —S(O)₂NH(C₁₋₆-alkyl);

-   A is halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl,    C₁₋₆-cyanoalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, C₁₋₆-thioalkyl,    —S(O)₂—C₁₋₆-alkyl, —S(O)—C₁₋₆-alkyl, nitro, hydroxy, cyano,    —(C₁₋₆-alkylene)-O—C₁₋₆-alkyl, —(C₁₋₆-alkylene)-O—C₁₋₆-haloalkyl,    —C(O)O—C₁₋₆-alkyl, —C(O)NR′R″, —S(O)₂NR′R″, —(CH₂)_(x)—NR′R″,    —(CH₂)_(x)—NR′C(O)—C₁₋₆-alkyl, or —(CH₂)_(x)—NR′S(O)₂—C₁₋₆-alkyl,    -   wherein x is from 0 to 4 and    -   R′ and R″ are each independently H or C₁₋₆-alkyl, or    -   R′ and R″ together with the nitrogen to which they are bound        form a 5 or 6-membered heterocycle comprising one or two        heteroatoms selected from N, O and S,    -   —(CH₂)_(y)—C₃₋₆-cycloalkyl, —(CH₂)_(y)-benzyl, or        —(CH₂)_(y)-phenyl,    -   wherein y is from 0 to 4, and    -   wherein benzyl or phenyl are optionally substituted with one,        two, or    -   three halo, C₁₋₆-haloalkyl, C₁₋₆-alkyl, or C₁₋₆-alkoxy;

-   R² is hydrogen, or C₁₋₆-alkyl;

-   R³, R⁴, R⁵, R⁶ are each independently hydrogen, halo, C₁₋₆-alkyl,    halo-C₁₋₆-alkyl, C₁₋₆-alkoxy or C₁₋₆-haloalkoxy;

-   R⁷, R⁸, R⁹, R¹⁰ are each independently hydrogen, halo, C₁₋₆-alkyl,    halo-C₁₋₆-alkyl, C₁₋₆-alkoxy or C₁₋₆-haloalkoxy;

-   or a pharmaceutically acceptable salt thereof,

-   with the proviso that compounds wherein R¹, R², R³, R⁴, R⁵ and R⁶    are all simultaneously hydrogen are excluded.

The invention further encompasses an embodiment of formula (I) wherein

-   -   X is CH₂, and Y is C═O,        -   X is O, and Y is C═O, or        -   X—Y is N═N;

-   R¹ is H,    -   C₂₋₆-alkyl, optionally substituted with CN or OH,    -   C₁₋₆-haloalkyl,    -   —(CR^(i)R^(ii))_(m)—R^(a),        -   wherein R^(i) and R^(ii) are independently from each other            H, methyl, or ethyl;        -   wherein m is from 1 to 4;        -   wherein R^(a) is            -   phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered                heterocycloalkyl                -   or 3 to 7-membered cycloalkyl,                -    which are optionally substituted with one or more                    A, or            -   —NR^(b)R^(c), wherein R^(b) and R^(c) are each                independently                -   hydrogen, C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, or                    —C(O)—C₁₋₆-alkyl,    -   —(CR^(iii)R^(iv))_(n)—C(O)R^(d),        -   wherein R^(iii) and R^(iv) are independently from each other            H, methyl, or ethyl;        -   wherein n is from 0 to 4;        -   wherein R^(d) is            -   C₁₋₆-alkoxy,            -   —NR^(e)R^(f), wherein R^(e) and R^(f) are each                independently                -   hydrogen,                -   C₁₋₆-alkyl, or                -   —(C₂₋₆-alkylene)NR^(g)R^(h); wherein R^(g) and R^(h)                    are each independently                -    hydrogen, C₁₋₆-alkyl, or —C(O)O—C₁₋₆-alkyl, or            -   phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered                heterocycloalkyl                -   or 3 to 7-membered cycloalkyl,                -    which are optionally substituted with one or more                    A,    -   —S(O)₂—C₁₋₆-alkyl,    -   —S(O)₂N(C₁₋₆-alkyl)₂, or    -   —S(O)₂NH(C₁₋₆-alkyl);

-   A is halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl,    C₁₋₆-cyanoalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, C₁₋₆-thioalkyl,    —S(O)₂—C₁₋₆-alkyl, cyano, —CH₂OCH₃, —C(O)O—C₁₋₆-alkyl, —C(O)NR′R″,    —S(O)₂NR′R″, —NR′C(O)—C₁₋₆-alkyl, —NR′S(O)₂—C₁₋₆-alkyl, benzyl, or    phenyl    -   wherein R′ and R″ are each independently H or C₁₋₆-alkyl.

-   R² is hydrogen, or C₁₋₆-alkyl;

-   R³, R⁴, R⁵, R⁶ are each independently hydrogen, halo, C₁₋₆-alkyl,    halo-C₁₋₆-alkyl, C₁₋₆-alkoxy or C₁₋₆-haloalkoxy;

-   R⁷, R⁸, R⁹, R¹⁰ are each independently hydrogen or halo;

-   or a pharmaceutically acceptable salt thereof,

-   with the proviso that compounds wherein R¹, R², R³, R⁴, R⁵ and R⁶    are all simultaneously hydrogen are excluded.

Preferred compounds of formula (I-a) are

-   1-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2-one,-   1-{1-[6-Chloro-1-(3,5-difluoro-benzyl)-1H-indole-3-carbonyl]-piperidin-4-yl}-1,3-dihydro-indol-2-one,-   2-{6-Chloro-3-[4-(2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide,-   2-(6-Chloro-3-{[4-(2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]carbonyl}-1H-indol-1-yl)-N,N-dimethylacetamide,-   2-{6-Chloro-3-[4-(2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-diethyl-acetamide,-   N-[2-(6-Chloro-3-{[4-(2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]carbonyl}-1H-indol-1-yl)ethyl]methanesulfonamide,-   N-[2-(6-Chloro-3-{[4-(2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]carbonyl}-1H-indol-1-yl)ethyl]acetamide,    and-   1-[1-(6-Chloro-2-methyl-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2-one,-   1-{1-[6-Chloro-1-(2-methylamino-ethyl)-1H-indole-3-carbonyl]-piperidin-4-yl}-1,3-dihydro-indol-2-one    hydrochloride, or-   1-{1-[6-Chloro-1-(2-dimethylamino-ethyl)-1H-indole-3-carbonyl]-piperidin-4-yl}-1,3-dihydro-indol-2-one.

Preferred compounds of formula (I-b) are

-   3-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-3H-benzooxazol-2-one,    and-   2-{6-Chloro-3-[4-(2-oxo-benzooxazol-3-yl)-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide.

Preferred compounds of formula (I-c) are

-   1-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2-one,-   2-(3-{[4-(1H-Benzotriazol-1-yl)piperidin-1-yl]carbonyl}-6-chloro-1H-indol-1-yl)-N-methylacetamide,-   2-(3-{[4-(1H-Benzotriazol-1-yl)piperidin-1-yl]carbonyl}-6-chloro-1H-indol-1-yl)-N,N-dimethylacetamide,-   (4-Benzotriazol-1-yl-piperidin-1-yl)-[6-chloro-1-(2-methylamino-ethyl)-1H-indol-3-yl]-methanone    hydrochloride,-   (4-Benzotriazol-1-yl-piperidin-1-yl)-[6-chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-methanone,    and-   (4-Benzotriazol-1-yl-piperidin-1-yl)-(7-chloro-2-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indol-10-yl)-methanone.

The invention also encompasses methods for the treatment ofdysmenorrhea, hypertension, chronic heart failure, inappropriatesecretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessivecompulsive disorder, anxiety and depressive disorders which comprisesadministering a therapeutically effective amount of a compound offormula (I), (Ia), (Ib), or (Ic).

The invention also encompasses a pharmaceutical composition comprising acompound of formula (I), (Ia), (Ib), or (Ic) and a pharmaceuticallyacceptable carrier. The pharmaceutical composition may further compriseat least one pharmaceutically acceptable excipient.

In a certain embodiment, the compounds of formula (I) of the inventioncan be manufactured according to a process comprising reacting acompound of formula (II):

with a compound of formula (III):

to obtain a compound of formula (I) wherein X, Y, R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹ and R¹⁰ are as defined hereinabove for formula (I).

In another embodiment, the compounds of formula (I) of the invention canbe manufactured according to a process comprising reacting a compound offormula (I-1), wherein R¹ equals H:

with a compound of formula R¹—Z (wherein R¹ is different from H), toobtain a compound of formula (I) wherein X, Y, R¹, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹ and R¹⁰ are as defined hereinabove for formula (I) and Z ishalo.

These processes are described in more details with the following generalschemes and procedures A to C.

General Scheme A

Compounds of formula (I) can be prepared via an amide coupling betweenan indole 3-carboxylic acid (II) and a compound of formula (III). Theusual reagents and protocols known in the art can be used to effect theamide coupling. Indole 3-carboxylic acids (II) are either commerciallyavailable or readily prepared using a procedure described in J. Med.Chem. 1991, 34, 140. Alternatively, they can be prepared following thegeneral scheme C as described hereinafter. The compounds of formula(III) are either commercially available or prepared using methods knownin the art starting from commercially available materials. Generalscheme A is hereinafter further illustrated with general procedures Iand II.

General Procedure B

Compounds of formula (I) with R¹ different from H can be prepared usingmethods known in the art, e.g. by N-deprotonation of a compound offormula (I-1) (compounds of formula (I) wherein R¹ is H) followed bytreatment with an electrophilic reactant R¹—Z (wherein Z is a leavinggroup, e.g. halo) which is either commercially available or easilyprepared according to methods well known in the art and commerciallyavailable starting materials. General scheme B is hereinafter furtherillustrated with general procedure III.

General Procedure C

The treatment of an indole derivative (IV-1) with trifluoroaceticanhydride in DMF affords intermediate (V) which can be hydrolysed withan aqueous sodium hydroxide solution to give the 3-carboxylic acidindole derivative (II-1). Alternatively, (V) could react with anelectrophilic reactant R¹—Z to give (VI), which is then converted to thecorresponding carboxylic acid derivative (II) with NaH/H₂O in DMF (seeJ. Org Chem., 1993, 10, 2862). Intermediate (VI) can alternatively beobtained by treatment of an indole derivative (IV-2) withtrifluoroacetic anhydride in a suitable solvent, e.g. DMF,dichloromethane or 1,2-dichloroethane. Addition of a suitable base maybe advantageous.

The compounds of the present invention exhibit V1a activity, which maybe detected as described below:

V1a Activity

Material & Method:

The human V1a receptor was cloned by RT-PCR from total human liver RNA.The coding sequence was subcloned in an expression vector aftersequencing to confirm the identity of the amplified sequence. Todemonstrate the affinity of the compounds from the present invention tothe human V1a receptor binding studies were performed. Cell membraneswere prepared from HEK293 cells transiently transfected with theexpression vector and grown in 20 liter fermenters with the followingprotocol.

50 g of cells were resuspended in 30 ml freshly prepared ice cold Lysisbuffer (50 mM HEPES, 1 mM EDTA, 10 mM MgCl2 adjusted to pH=7.4+ completecocktail of protease inhibitor (Roche Diagnostics)); homogenized withPolytron for 1 min; and sonicated on ice for 2×2 minutes at 80%intensity (Vibracell sonicator). The preparation was centrifuged 20 minat 500 g at 4° C., the pellet was discarded and the supernatantcentrifuged 1 hour at 43'000 g at 4° C. (19'000 rpm). The pellet wasresuspended in 12.5 ml Lysis buffer+12.5 ml Sucrose 20% and homogenizedusing a Polytron for 1-2 min. The protein concentration was determinedby the Bradford method and aliquots were stored at −80° C. until use.For binding studies 60 mg Yttrium silicate SPA beads (Amersham) weremixed with an aliquot of membrane in binding buffer (50 mM Tris, 120 mMNaCl, 5 mM KCl, 2 mM CaCl2, 10 mM MgCl2) for 15 minutes with mixing. 50ul of bead/membrane mixture was then added to each well of a 96 wellplate, followed by 50 ul of 4 nM 3H-Vasopressin (American RadiolabeledChemicals). For total binding measurement 100 ul of binding buffer wereadded to the respective wells, for non-specific binding 100 ul of 8.4 mMcold vasopressin and for compound testing 100 ul of a serial dilution ofeach compound in 2% DMSO. The plate was incubated 1 h at roomtemperature, centrifuged 1 min at 1000 g and counted on a PackardTop-Count. Non-specific binding counts were subtracted from each well,and data was normalized to the maximum specific binding set at 100%. Tocalculate an IC 50 the curve was fitted using a non-linear regressionmodel (XLfit), and the Ki was calculated using the Cheng-Prussoffequation.

Example No pKi hV1a 1 8.05 2 8.59 3 8.74 4 8.89 5 7.93 6 8.5 7 7.93 87.9 10 8.17 13 7.85 14 8.18 15 8.68 17 7.71 18 7.68

The present invention also provides pharmaceutical compositionscontaining compounds of the invention, for example compounds of formulae(I-a) to (I-e), or pharmaceutically acceptable salts thereof and apharmaceutically acceptable carrier. Such pharmaceutical compositionscan be in the form of tablets, coated tablets, dragées, hard and softgelatine capsules, solutions, emulsions or suspensions. Thepharmaceutical compositions also can be in the form of suppositories orinjectable solutions.

The pharmaceutical compositions of the invention, in addition to one ormore compounds of the invention, contain a pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers includepharmaceutically inert, inorganic or organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts etc canbe used as such excipients e.g. for tablets, dragées and hard gelatinecapsules. Suitable excipients for soft gelatine capsules are e.g.vegetable oils, waxes, fats, semi-solid and liquid polyols etc. Suitableexcipients for the manufacture of solutions and syrups are e.g. water,polyols, saccharose, invert sugar, glucose etc. Suitable excipients forinjection solutions are e.g. water, alcohols, polyols, glycerol,vegetable oils etc. Suitable excipients for suppositories are e.g.natural or hardened oils, waxes, fats, semi-liquid or liquid polyolsetc.

Moreover, the pharmaceutical compositions can contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

The dosage at which compounds of the invention can be administered canvary within wide limits and will, of course, be fitted to the individualrequirements in each particular case. In general, in the case of oraladministration a daily dosage of about 10 to 1000 mg per person of acompound of general formula (I) should be appropriate, although theabove upper limit can also be exceeded when necessary.

The following Examples illustrate the present invention without limitingit. All temperatures are given in degrees Celsius.

Example A

Tablets of the following composition can be manufactured in the usualmanner:

mg/tablet Active substance 5 Lactose 45 Corn starch 15 Microcrystallinecellulose 34 Magnesium stearate 1 Tablet weight 100

Example B

Capsules of the following composition can be manufactured:

mg/capsule Active substance 10 Lactose 155 Corn starch 30 Talc 5 Capsulefill weight 200

The active substance, lactose and corn starch can be firstly mixed in amixer and then in a comminuting machine. The mixture can be returned tothe mixer, the talc can be added thereto and mixed thoroughly. Themixture can be filled by machine into hard gelatine capsules.

Example C

Suppositories of the following composition can be manufactured:

mg/supp. Active substance 15 Suppository mass 1285 Total 1300

The suppository mass can be melted in a glass or steel vessel, mixedthoroughly and cooled to 45° C.

Thereupon, the finely powdered active substance can be added thereto andstirred until it has dispersed completely. The mixture can be pouredinto suppository moulds of suitable size, left to cool; thesuppositories then can be removed from the moulds and packedindividually in wax paper or metal foil.

In the following, the synthesis of compounds of formula (I) is furtherexemplified: The compounds of formula I may be prepared in accordancewith the process variants as described above. The starting materialsdescribed in the Example section are either commercially available orare otherwise known or derived from the chemical literature, forinstance as cited below, or may be prepared as described in the Examplessection.

Examples Acid Intermediates of Formula II and II-1 Acid 16-Chloro-1H-indole-3-carboxylic acid a)1-(6-Chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone

To a solution of 1.0 g (6.6 mmol) 6-chloroindole in 13 ml DMF were addeddropwise at 0° C. 2.75 ml (19.8 mmol) trifluoroacetic anhydride.Stirring at this temperature for 90 min. was followed by quenching with30 ml of a 2 M aqueous solution of sodium carbonate, dilution with 50 mlwater and extraction with three 100-ml portions of tert-butyl methylether. The combined organic layers were dried over sodium sulfate,filtered and concentrated to give 1.3 g (80%) of the crude titlecompound as an off-white solid.

ES-MS m/e (%): 246 (M−H⁺).

b) 6-Chloro-1H-indole-3-carboxylic acid

A mixture of 1.3 g (5.3 mmol)1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone and 26.5 ml of a 4 Maqueous solution of sodium hydroxide was heated at reflux for 4.5 h. Themixture was cooled to room temperature and washed with two 100-mlportions of tert-butyl methyl ether. The aqueous layer was acidified topH 2-3 by addition of concentrated hydrochloric acid solution at 0° C.Extraction with three 100-ml portions of tert-butyl methyl ether, dryingover sodium sulfate, filtration and concentration in vacuo gave 0.80 g(78%) of the crude title compound as a brown solid.

ES-MS m/e (%): 194 (M−H⁺).

Acid 2 6-Chloro-1-(3,5-difluoro-benzyl)-1H-indole-3-carboxylic acid a)1-[6-Chloro-1-(3,5-difluoro-benzyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanone

A mixture of 2.0 g (9.4 mmol)1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, 4.59 g (14.1 mmol)cesium carbonate and 2.14 g (10.4 mmol) 3,5-difluorobenzyl bromide in 90ml acetonitrile was heated at 80° C. for 3 h. After cooling to roomtemperature addition of 150 ml water was followed by extraction withthree 150-ml portions of tert-butyl methyl ether. The combined organiclayers were dried over sodium sulfate, filtered and concentrated invacuo. The residue was triturated in 30 ml hot cyclohexane. Filtrationgave 2.2 g (64%) of the crude title compound as light brown solid.

ES-MS m/e (%): 372 (M−H⁺).

b) 6-Chloro-1-(3,5-difluoro-benzyl)-1H-indole-3-carboxylic acid

To a solution of 2.2 g (6.5 mmol)1-[6-chloro-1-(3,5-difluoro-benzyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanonein 65 ml DMF were added 1.7 g (36 mmol) sodium hydride (50% in oil) atroom temperature. After stirring for 5 min. 0.59 ml (33 mmol) water wereadded dropwise. Stirring was continued at room temperature for 45 min.The reaction mixture was diluted with 150 ml of tert-butyl methyl etherand extracted with two 150-ml portions of a 1 M aqueous solution ofsodium hydroxide. The combined aqueous layers were acidified to pH 1with concentrated hydrochloric acid solution and extracted with three150-ml portions of ethyl acetate. The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was dried in high vacuo at 80° C. to give 2.0 g (95%) of thecrude title compound as a brown solid.

ES-MS m/e (%): 320 (M−H⁺).

Acid 3 6-Chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid

a) 2-[6-Chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N-methyl-acetamide

Following general procedure II, the alkylation of1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, with (commerciallyavailable) 2-chloro-N-methyl-acetamide gave the title compound.

ES-MS m/e (%): 319.3 (M+H⁺).

b) 6-Chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid

2-[6-Chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N-methyl-acetamidewas suspensed in DCE and treated with (2.2 eq.) of sodiumtrimethylsilanolate. After shaking at room temperature for 20 min, themixture was concentrated in vacuo and purified by prep. HPLC to give thetitle compound in 27% yield.

ES-MS m/e (%): 265.0 (M−H⁺).

Acid 4 6-Chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid

a)2-[6-Chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl-acetamide

To a stirred solution of1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (0.75 g) in 20 ml ofDMF at 0° C., were added 128 mg (1.1 eq.) of NaH (60% in oil). Themixture was stirred for 30 min. and then 0.32 ml (1.1 eq.) ofdimethylamino-acetyl chloride were added. The mixture was stirred anadditional hour and then poured onto water and extracted with ethylacetate. The combined organic phases were dried over Na₂SO₄ andconcentrated in vacuo to afford 598 mg (61%) of2-[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl-acetamideas a white solid.

b) 6-Chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid

Using the procedure described for the preparation of6-chloro-1-(3,5-difluoro-benzyl)-1H-indole-3-carboxylic acid, from 0.50g of2-[6-chloro-5-methyl-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl-acetamidewere prepared 0.38 g (76%) of6-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid as awhite solid.

Acid 5 6-Chloro-2-methyl-1H-indole-3-carboxylic acid a)(6-Chloro-1H-indol-2-yl)-methanol

To a solution of 2.00 g (8.94 mmol) 6-chlorindole-2-carboxylic acidethyl ester in 50 ml diethyl ether were added 0.475 g (12.5 mmol)lithium aluminum hydride at 0° C. The reaction mixture was heated atreflux for 45 min and quenched by consecutive addition of 10 ml water,10 ml aqueous 2 M sodium hydroxide solution and 10 ml water at 0° C. Theaqueous layer was extracted with tert-butyl methyl ether (3×100 ml). Thecombined organic layers were dried over sodium sulfate and concentratedin vacuo to give the crude title compound (1.64 g; 100%) as a whitesolid.

MS m/e (%): 180 (M−H⁺, 100).

b) 6-Chloro-2-methyl-1H-indole

A solution of 1.60 g (8.81 mmol) (6-chloro-1H-indol-2-yl)-methanol in 5ml 1,2-dichloroethane was added to a mixture of 80.0 ml trifluoroaceticacid and 32.0 ml triethylsilane at 65° C. After 5 min, the reactionmixture was cooled to room temperature and quenched with water. The pHwas adjusted to 14 by the addition of aqueous sodium hydroxide solution(32%). The aqueous layer was extracted with tert-butyl methyl ether(3×200 ml). The combined organic layers were dried over sodium sulfateand concentrated in vacuo. The residue was purified byflash-chromatography (aminopropyl-modified silica gel, n-heptane/ethylacetate) to give the title compound (0.39 g; 27%) as a white solid.

MS m/e (%): 164 (M−H⁺, 100).

c) 1-(6-Chloro-2-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone

To a solution of 0.38 g (2.3 mmol) 6-chloro-2-methyl-1H-indole in 20 ml1,2-dichloroethane at 0° C. were added 0.35 ml (2.5 mmol)trifluoroacetic anhydride. The reaction mixture was quenched withaqueous 2 M sodium carbonate solution after 30 min and extracted withdichloromethane (3×100 ml). The combined organic layers were dried oversodium sulfate and concentrated in vacuo to give the title compound(0.57 g; 95%) as an off-white solid.

MS m/e (%): 260 (M−H⁺, 100).

d) 6-Chloro-2-methyl-1H-indole-3-carboxylic acid

A solution of 0.57 g (2.2 mmol)1-(6-chloro-2-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in 21.7 ml(86.8 mmol) aqueous 4 M sodium hydroxide solution was heated at refluxfor 45 min. After cooling to room temperature the reaction mixture wasdiluted with water and extracted with tert-butyl methyl ether (2×50 ml).The aqueous layer was cooled to 0-5° C., acidified (pH 1-2) withconcentrated aqueous hydrochloric acid solution and extracted with ethylacetate (3×100 ml). The combined ethyl acetate layers were dried oversodium sulfate and concentrated in vacuo to give the title compound(0.14 g, 31%) as an off-white solid.

MS m/e (%): 208 (M−H⁺, 100).

Acid 61-[2-(tert-Butoxycarbonyl-methyl-amino)-ethyl]-6-chloro-1H-indole-3-carboxylicacid a){2-[6-Chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-ethyl}-carbamic acidtert-butyl ester

To a solution of 11.5 g (46.4 mmol)1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in 150 mlN,N-dimethylformamide were slowly added 6.25 g (55.7 mmol) potassiumtert-butylate. The temperature was kept below 32° C. The reactionmixture was allowed to cool to room temperature and stirred for 20 min.To the resulting brown suspension were added slowly 12.4 g (55.7 mmol)2,2-dioxo-2λ⁶-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.The reaction mixture was stirred at room temperature until completeconsumption of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone,which was monitored by thin layer chromatography. Dilution with 300 mltert-butyl methyl ether was followed by washing with 250 ml of a 0.2 Maqueous solution of hydrochloric acid. The aqueous layer was extractedwith two 200-ml portions of tert-butyl methyl ether. The combinedorganic layers were washed with water and brine, dried over sodiumsulfate and concentrated in vacuo. The residue, 19.5 g of a light brownsolid, was triturated with 300 ml of warm tert-butyl methyl ether. Aftercooling to room temperature the precipitate was collected by filtration,washed with cold tert-butyl methyl ether and dried in vacuo to give 11.1g (61%) of the title compound as an off-white solid. The filtrate wasconcentrated to dryness. The residue was triturated with 50 ml warmtert-butyl methyl ether. After cooling to room temperature theprecipitate was collected by filtration, washed with cold tert-butylmethyl ether and dried in vacuo to give another 3.5 g (19%) of the titlecompound as an off-white solid.

MS m/e (%): 387 (M−H⁺, 87).

b){2-[6-Chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-ethyl}-methyl-carbamicacid tert-butyl ester

To a solution of 14.1 g (36.1 mmol){2-[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-ethyl}-carbamic acidtert-butyl ester in 360 ml dry tetrahydrofuran were slowly added 44 ml(40 mmol) of a 0.91 M solution of potassium hexamethyldisilazide intetrahydrofuran at −78° C. After stirring for 20 min. were added 2.5 ml(40 mmol) iodomethane at −78° C. Stirring was continued for 15 min. at−78° C. The cooling bath was removed and the mixture was stirred foranother 3 h at room temperature. Quenching with water was followed byevaporation of the solvent in a rotary evaporator. The residue wasdiluted with a mixture of 200 ml water and 100 ml of a saturated aqueoussolution of ammonium chloride. After extraction with three 250-mlportions of tert-butyl methyl ether the combined organic extracts werewashed with 200 ml of an ice-cold 0.2 M aqueous solution of hydrochloricacid and 100 ml brine, dried over sodium sulfate and concentrated invacuo to give 14.9 g of the crude product as a brown oil.

MS m/e (%): 349 ((M-C4H8)+H⁺, 100).

c)1-[2-(tert-Butoxycarbonyl-methyl-amino)-ethyl]-6-chloro-1H-indole-3-carboxylicacid

To a solution of 15.4 g (38.0 mmol) crude{2-[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-ethyl}-methyl-carbamicacid tert-butyl ester in 380 ml N,N-dimethylformamide were slowly added11.0 g (228 mmol) sodium hydride (50%, dispersion in oil) followed by3.40 ml (190 mmol) water at 15-22° C. After stirring for 1 h at roomtemperature 500 ml water were added slowly. The mixture was washed withtwo 300-ml portions of tert-butyl methyl ether. The combined organiclayers were extracted with 300 ml of a 0.5 M aqueous solution of sodiumhydroxide. The combined aqueous layers were acidified to pH 2 with anice-cold 4 M aqueous solution of hydrochloric acid at 0-5° C. andextracted with two 400-ml portions of ethyl acetate.

The organic extracts were dried over sodium sulfate and concentrated invacuo to give 11.3 g (84.3%) of the title compound as a light yellowsolid.

MS m/e (%): 351 (M−H⁺, 100).

Examples

Amide Coupling:

General procedure I:

To a stirred solution of an indole-3-carboxylic acid derivative (1 mmol)in 10 ml CH₂Cl₂ are added (1.3 mmol) EDC, (1.3 mmol) HOBt, (1.3 mmol)triethylamine and (1 mmol) of the amine derivative. The mixture isstirred overnight at RT and then poured onto water and extracted withCH₂Cl₂. The combined organic phases are dried over Na₂SO₄ andconcentrated in vacuo. Flash chromatography or preparative HPLC affordsan amide derivative of formula (I).

General Procedure II:

To a solution of an indole-3-carboxylic acid derivative (0.13 mmol),N-ethyl diisopropyl amine (0.14 mmol) and TBTU or HATU (0.14 mmol) in 2ml dry N,N-dimethylformamide is added the amine derivative (0.14 mmol)at RT. The reaction mixture is quenched with 0.5 M aqueous sodiumhydroxide (20 ml) after 2 h and extracted with ethyl acetate (2×30 ml).The combined organic layers are washed with water (2×30 ml) and brine(1×30 ml), dried over sodium sulfate and concentrated to dryness. Flashchromatography or preparative HPLC affords an amide derivative offormula (I).

Indole-N-alkylation:

General Procedure III:

To a stirred solution of an indole of formula (I-1) wherein R¹ is H inDMF are added 2. 1 eq. NaH (60% in oil). The mixture is stirred at RTfor 30 min. and then the electrophilic reagent R¹—Z (1.1 eq.) is added.The mixture is stirred an additional 14 hours at 60° C. and then pouredonto water and extracted with ethyl acetate. The combined organic phasesare dried over Na₂SO₄ and concentrated in vacuo. Purification bypreparative HPLC affords compounds of formula (I) with R¹ different fromH.

Example 11-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2-one

Amide coupling according to general procedure I:

Amine: 1-Piperidin-4-yl-1,3-dihydro-indol-2-one,

Acid: 6-Chloro-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 393.9 (M+H⁺).

Example 21-{1-[6-Chloro-1-(3,5-difluoro-benzyl)-1H-indole-3-carbonyl]-piperidin-4-yl}-1,3-dihydro-indol-2-one

To a suspension of 0.10 g (0.31 mmol)6-chloro-1-(3,5-difluoro-benzyl)-1H-indole-3-carboxylic acid and onedrop of DMF in 2 ml dichloromethane were added dropwise at 0° C. 0.032ml (0.37 mmol) oxalyl chloride. The mixture was allowed to warm to roomtemperature, stirred for 1 h and subsequently added dropwise to asolution of 74 mg (0.34 mmol) 1-piperidin-4-yl-1,3-dihydro-indol-2-oneand 63 mg (0.62 mmol) triethylamine in 1 ml dichloromethane at roomtemperature. After stirring over night the reaction mixture wasconcentrated and the residue was purified by flash chromatography togive 78 mg (48%) of the title compound as a light yellow solid.

ES-MS m/e (%): 521 (M+H⁺).

Example 32-{6-Chloro-3-[4-(2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Amide coupling according to general procedure II:

Amine: 1-Piperidin-4-yl-1,3-dihydro-2H-indol-2-one,

Acid: 6-Chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 465 (M+H⁺, 100).

Example 42-(6-Chloro-3-{[4-(2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]carbonyl}-1H-indol-1-yl)-N,N-dimethylacetamide

Amide coupling according to general procedure I:

Amine: 1-Piperidin-4-yl-1,3-dihydro-indol-2-one (CAS: 16223-25-9),

Acid: 6-Chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 479.2 (M+H⁺).

Example 52-{6-Chloro-3-[4-(2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-diethyl-acetamide

A solution of1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydroindol-2-one(1 eq) in dry DMF was treated with NaH (1.1 eq) at RT for 15 mins andthen a solution of 2-chloro-N,N-diethyl-acetamide (3.3 eq) andtriethylamine (3.3 eq) in three portions and the mixture heated to 60°C. for 6 h. Concentration and purification by prep HPLC gave the titlecompound.

ES-MS m/e (%): 507.5 (M+H⁺).

Example 6N-[2-(6-Chloro-3-{[4-(2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]carbonyl}-1H-indol-1-yl)ethyl]methanesulfonamide

a)1-{1-[1-(2-Amino-ethyl)-6-chloro-1H-indole-3-carbonyl]-piperidin-4-yl}-1,3-dihydro-indol-2-one

A solution of1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2-one(1 eq) in dry DMF was treated with NaH (1.1 eq) at 0° C. for 60 min. andthen a solution of 2,2-dioxo-2λ6-[1,2,3]oxathiazolidine-3-carboxylicacid tert-butyl ester (1.1 eq) and triethylamine (1.1 eq) in dry DMF wasadded and the mixture stirred at RT for 2 h. After concentration themixture was treated with 4 M HCl in dioxan (5 eq) at 50° C. for 1 h,evaporated to dryness and partitioned between ethyl acetate and 1 NNaHCO₃. The organic layer was washed with brine, separated, evaporatedand the crude product chromatographed on silica gel (CH₂Cl₂-MeOH) togive the title compound.

ES-MS m/e (%): 437.0 (M+H⁺).

b)N-[2-(6-Chloro-3-{[4-(2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]carbonyl}-1H-indol-1-yl)ethyl]methanesulfonamide

A solution of1-{1-[1-(2-amino-ethyl)-6-chloro-1H-indole-3-carbonyl]-piperidin-4-yl}-1,3-dihydro-indol-2-one(1 eq) in dry CH₂Cl₂ was treated with methanesulfonyl chloride (1.1 eq)and triethylamine at RT for 15 h. Quenching with H₂O and extraction intoCH₂Cl₂ followed by concentration and purification by prep HPLC gave thetitle compound.

ES-MS m/e (%): 515.2 (M+H⁺).

Example 7N-[2-(6-Chloro-3-{[4-(2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]carbonyl}-1H-indol-1-yl)ethyl]acetamide

A solution of1-{1-[1-(2-amino-ethyl)-6-chloro-1H-indole-3-carbonyl]-piperidin-4-yl}-1,3-dihydro-indol-2-one(1 eq) in dry CH₂Cl₂ was treated with acetyl chloride (1.1 eq) andtriethylamine at RT for 15 h. Quenching with H₂O and extraction intoCH₂Cl₂ followed by concentration and purification by prep HPLC gave thetitle compound.

ES-MS m/e (%): 479.2 (M+H⁺).

Example 81-[1-(6-Chloro-2-methyl-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2-one

Amide coupling according to general procedure II:

Amine: 1-Piperidin-4-yl-1,3-dihydro-2H-indol-2-one,

Acid: 6-Chloro-2-methyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 406 (M−H⁺, 100).

Example 93-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-3H-benzooxazol-2-one

Amide coupling according to general procedure II:

Amine: 3-Piperidin-4-yl-3H-benzooxazol-2-one (preparation described inWO 95/28397),

Acid: 6-Chloro-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 394 (M−H⁺, 100).

Example 102-{6-Chloro-3-[4-(2-oxo-benzooxazol-3-yl)-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Amide coupling according to general procedure II:

Amine: 3-Piperidin-4-yl-3H-benzooxazol-2-one (preparation described inWO 95/28397),

Acid: 6-Chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 467 (M+H⁺, 100).

Example 111-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2-one

Amide coupling according to general procedure I:

Amine:(4-Benzotriazol-1-yl-piperidin-1-yl)-(6-chloro-1H-indol-3-yl)-methanone,

Acid: 6-Chloro-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 380.4 (M+H⁺).

Example 122-(3-{[4-(1H-Benzotriazol-1-yl)piperidin-1-yl]carbonyl}-6-chloro-1H-indol-1-yl)-N-methylacetamide

Amide coupling according to general procedure I:

Amine:1-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2-one,

Acid: 6-Chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid acid,

ES-MS m/e (%): 451.2 (M+H⁺).

Example 132-(3-{[4-(1H-Benzotriazol-1-yl)piperidin-1-yl]carbonyl}-6-chloro-1H-indol-1-yl)-N,N-dimethylacetamide

Amide coupling according to general procedure I:

Amine: 1-Piperidin-4-yl-1H-benzotriazole,

Acid: 6-Chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 465.1 (M+H⁺).

Example 141-{1-[6-Chloro-1-(2-methylamino-ethyl)-1H-indole-3-carbonyl]-piperidin-4-yl}-1,3-dihydro-indol-2-onehydrochloride a)(2-{6-Chloro-3-[4-(2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-ethyl)-methyl-carbamicacid tert-butyl ester

To a solution of 0.20 g (0.57 mmol)1-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-6-chloro-1H-indole-3-carboxylicacid, 0.11 ml (0.63 mmol) N,N-diisopropylethylamine and 2 drops ofN,N-dimethylformamide in 4 ml dicholormethane were added 0.060 ml (0.74mmol) oxalyl chloride at 0-5° C. After completed addition the reactionmixture was allowed to warm to room temperature and stirred for 3 h. Asolution of 0.15 g (0.68 mmol)1,3-dihydro-1-(piperidin-4-yl)-(2H)-indol-2-one and 0.11 ml (0.63 mmol)N,N-diisopropylethylamine in 2 ml dicholormethane was added. Afterstirring for 15 min at room temperature silica gel was added to thereaction mixture and the solvent was evaporated in vacuo. The residuewas transferred to a silica gel column. Elution gave 0.26 g (82%) of thetitle compound as an off-white solid.

ES-MS m/e (%): 551 (M+H⁺, 39).

b)1-{1-[6-Chloro-1-(2-methylamino-ethyl)-1H-indole-3-carbonyl]-piperidin-4-yl}-1,3-dihydro-indol-2-onehydrochloride

A solution of 0.25 g (0.45 mmol)(2-{6-chloro-3-[4-(2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-ethyl)-methyl-carbamicacid tert-butyl ester in 3.6 ml (4.5 mmol) of a 1.25 M solution ofhydrochloric acid in methanol was stirred for 20 min. at 50° C. Thereaction mixture was concentrated to dryness to give 0.21 g of the titlecompound as an off-white solid.

ES-MS m/e (%): 451 (M+H⁺, 100).

Example 151-{1-[6-Chloro-1-(2-dimethylamino-ethyl)-1H-indole-3-carbonyl]-piperidin-4-yl}-1,3-dihydro-indol-2-one

A suspension of 0.40 g (1.0 mmol)1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2-one,0.16 g (1.1 mmol) 1-chloro-2-dimethylaminoethane hydrochloride and 0.69g (2.1 mmol) cesium carbonate in 10 ml acetonitrile was heated at 50° C.over night. After cooling to room temperature the reaction mixture wasdiluted with a 0.5 M aqueous solution of sodium hydroxide and extractedwith three portions of ethyl acetate. The combined organic extracts werewashed with brine, dried over sodium sulfate and concentrated in vacuo.Flash chromatography gave 0.18 g (39%) of the title compound.

ES-MS m/e (%): 466 (M+H⁺, 100).

Example 16(4-Benzotriazol-1-yl-piperidin-1-yl)-[6-chloro-1-(2-methylamino-ethyl)-1H-indol-3-yl]-methanonehydrochloride

The title compound was prepared according to the procedures describedfor the preparation of1-{1-[6-chloro-1-(2-methylamino-ethyl)-1H-indole-3-carbonyl]-piperidin-4-yl}-1,3-dihydro-indol-2-onehydrochloride using 1-(4-piperidyl)-1H-1,2,3-benzotriazole hydrochlorideinstead of 1,3-dihydro-1-(piperidin-4-yl)-(2H)-indol-2-one and a totalof 3.2 molar equivalents of N,N-diisopropylethylamine instead of 2.2molar equivalents in step a).

ES-MS m/e (%): 437 (M+H⁺, 100).

Example 17(4-Benzotriazol-1-yl-piperidin-1-yl)-[6-chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-methanone

and

Example 18(4-Benzotriazol-1-yl-piperidin-1-yl)-(7-chloro-2-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indol-10-yl)-methanone

A mixture of 0.20 g (0.41 mmol)(4-benzotriazol-1-yl-piperidin-1-yl)-[6-chloro-1-(2-methylamino-ethyl)-1H-indol-3-yl]-methanonehydrochloride, 0.057 ml (0.41 mmol) triethylamine and 0.10 g (3.3 mmol)paraformaldehyde in 4 ml methanol was heated at reflux for 7 h. Aftercooling to 0° C. 0. were added 052 g (0.82 mmol) sodiumcyanoborohydride. The cooling bath was removed and the reaction mixturewas stirred at room temperature for 16 h. Quenching with 1 M aqueoussodium hydroxide solution was followed by extraction with two portionsof ethyl acetate. The combined organic extracts were dried over sodiumsulfate and concentrated in vacuo. Flash chromatography gave 0.040 g(22%)(4-benzotriazol-1-yl-piperidin-1-yl)-[6-chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-methanoneas a white solid (ES-MS m/e (%): 451 (M+H⁺, 100)) and 0.11 g (60%)(4-benzotriazol-1-yl-piperidin-1-yl)-(7-chloro-2-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indol-10-yl)-methanoneas a white solid (ES-MS m/e (%): 449 (M+H⁺, 100)).

1. A compound of formula (I-b)

wherein R¹ is H, C₁₋₁₂-alkyl, optionally substituted with CN or OH,C₁₋₆-haloalkyl, C₂₋₁₂-alkenyl, —(CR^(i)R^(ii))_(m)—R^(a), wherein R^(i)and R^(ii) are independently from each other H, methyl, or ethyl;wherein m is from 0 to 4; wherein R^(a) is phenyl, 5- to 6-memberedheteroaryl, 3- to 7-membered heterocycloalkyl or 3 to 7-memberedcylcoalkyl,  which are optionally substituted with one or more A, or—NR^(b)R^(c), wherein R^(b) and R^(c) are each independently hydrogen,hydroxy, C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, or —C(O)—C₁₋₆-alkyl,—(CR^(iii)R^(iv))_(n)—C(O)R^(d), wherein R^(iii) and R^(iv) areindependently from each other H, methyl, or ethyl; wherein n is from 0to 4; wherein R^(d) is C₁₋₆-alkoxy, —NR^(e)R^(f), wherein R^(e) andR^(f) are each independently hydrogen, C₁₋₆-alkyl, or—(C₂₋₆-alkylene)NR^(g)R^(h); wherein R^(g) and R^(h) are eachindependently hydrogen, C₁₋₆-alkyl, or —C(O)O—C₁₋₆-alkyl, phenyl, 5- to6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to7-membered cycloalkyl, which are optionally substituted with one or moreA, —S(O)₂-phenyl, wherein phenyl is optionally substituted with one ormore halo, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, nitro, hydroxyor cyano; —S(O)₂—C₁₋₆-alkyl, —S(O)₂N(C₁₋₆-alkyl)₂, —S(O)₂NH(C₁₋₆-alkyl);A is halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl,C₁₋₆-cyanoalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, —S(O)₀₋₂C₁₋₆-alkyl,nitro, hydroxy, cyano, —(C₁₋₆-alkylene)-O—C₁₋₆-alkyl,—(C₁₋₆-alkylene)-O—C₁₋₆-haloalkyl, —(C₁₋₆-alkylene)-OR′″,—C(O)OC₁₋₆-alkyl, —C(O)OR′″, —C(O)R′″, —C(O)NR′R″, —S(O)₂NR′R″,—(CH₂)_(x)—NR′R″, —(CH₂)_(x)—NR′C(O)—C₁₋₆-alkyl,—(CH₂)_(x)—NR′S(O)₂—C₁₋₆-alkyl, —(CH₂)_(x)—C₃₋₆-cycloalkyl,—(CH₂)_(x)—R′″, wherein x is from 0 to 4, R′ and R″ are eachindependently H or C₁₋₆-alkyl, or R′ and R″ together with the nitrogento which they are bound form a 5 or 6-membered heterocycle comprisingone or two heteroatoms selected from N, O and S, and R′″ is phenyl or 5-to 6-membered heteroaryl, optionally substituted with one, two, or threehalo, C₁₋₆-haloalkyl, C₁₋₆-alkyl, or C₁₋₆-alkoxy, R² is hydrogen,C₁₋₆-alkyl, —C(O)R^(n), wherein R^(n) is C₁₋₆-alkyl, 3 to 7-memberedheterocycloalkyl, optionally substituted with one, two or threeC₁₋₆-alkyl, —C(O)O—C₁₋₆-alkyl, or —S(O)₂—C₁₋₆-alkyl, NR^(j)R^(k),wherein R^(j) and R^(k) are each independently hydrogen, C₁₋₆-alkyl,—(C₂₋₆-alkylene)-NR^(l)R^(m); wherein R^(l) and R^(m) are eachindependently hydrogen, C₁₋₆-alkyl, or —C(O)O—C₁₋₆-alkyl; or R³, R⁴, R⁵,R⁶ are each independently hydrogen, halo, C₁₋₆-alkyl, halo-C₁₋₆-alkyl,C₁₋₆-alkoxy or C₁₋₆-haloalkoxy; R⁷, R⁸, R⁹, R¹⁰ are each independentlyhydrogen, halo, C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁₋₆-alkoxy orC₁₋₆-haloalkoxy; or a pharmaceutically acceptable salt thereof, with theproviso that compounds wherein R¹, R², R³, R⁴, R⁵ and R⁶ are allsimultaneously hydrogen are excluded.
 2. A compound of claim 1, whereinR¹ is H, C₂₋₆-alkyl, optionally substituted with CN or OH,C₁₋₆-haloalkyl, —(CR^(i)R^(ii))_(m)—R^(a), wherein R^(i) and R^(ii) areindependently from each other H, methyl, or ethyl; wherein m is from 0to 4; wherein R^(a) is phenyl, 5- to 6-membered heteroaryl, 3- to7-membered heterocycloalkyl or 3 to 7-membered cycloalkyl, which areoptionally substituted with one or more A, or —NR^(b)R^(c), whereinR^(b) and R^(c) are each independently hydrogen, C₁₋₆-alkyl,—S(O)₂—C₁₋₆-alkyl, or —C(O)—C₁₋₆-alkyl, —(CR^(iii)R^(iv))_(n)—C(O)R^(d),wherein R^(iii) and R^(iv) are independently from each other H, methyl,or ethyl; wherein n is from 0 to 4; wherein R^(d) is C₁₋₆-alkoxy,—NR^(e)R^(f), wherein R^(e) and R^(f) are each independently hydrogen,C₁₋₆-alkyl, or —(C₂₋₆-alkylene)NR^(g)R^(h); wherein R^(g) and R^(h) areeach independently hydrogen, C₁₋₆-alkyl, or —C(O)O—C₁₋₆-alkyl, phenyl,5- to 6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to7-membered cycloalkyl, which are optionally substituted with one or moreA, —S(O)₂—C₁₋₆-alkyl, —S(O)₂N(C₁₋₆-alkyl)₂, —S(O)₂NH(C₁₋₆-alkyl); A ishalo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl, C₁₋₆-cyanoalkyl,C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, —S(O)₀₋₂C₁₋₆-alkyl, nitro, hydroxy, cyano,—(C₁₋₆-alkylene)-O—C₁₋₆-alkyl, —(C₁₋₆-alkylene)-O—C₁₋₆-haloalkyl,—(C₁₋₆-alkylene)-OR′″, —C(O)OC₁₋₆-alkyl, —C(O)OR′″, —C(O)R′″,—C(O)NR′R″, —S(O)₂NR′R″, —(CH₂)_(x)—NR′R″,—(CH₂)_(x)—NR′C(O)—C₁₋₆-alkyl, —(CH₂)_(x)—NR′S(O)₂—C₁₋₆-alkyl,—(CH₂)_(x)—C₃₋₆-cycloalkyl, —(CH₂)_(x)—R′″, wherein x is from 0 to 4, R′and R″ are each independently H or C₁₋₆-alkyl, or R′ and R″ togetherwith the nitrogen to which they are bound form a 5 or 6-memberedheterocycle comprising one or two heteroatoms selected from N, O and S,and R′″ is phenyl or 5- to 6-membered heteroaryl, optionally substitutedwith one, two, or three halo, C₁₋₆-haloalkyl, C₁₋₆-alkyl, orC₁₋₆-alkoxy.
 3. The compound of claim 1, wherein R¹ is H, C₂₋₆-alkyl,optionally substituted with CN or OH, C₁₋₆-haloalkyl,—(CR^(i)R^(ii))_(m)—R^(a), wherein R^(i) and R^(ii) are independentlyfrom each other H, methyl, or ethyl; wherein m is from 1 to 4; whereinR^(a) is phenyl, 5- to 6-membered heteroaryl, 3- to 7-memberedheterocycloalkyl or 3 to 7-membered cycloalkyl,  which are optionallysubstituted with one or more A, or —NR^(b)R^(c), wherein R^(b) and R^(c)are each independently hydrogen, C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, or—C(O)—C₁₋₆-alkyl, —(CR^(iii)R^(iv))_(n)—C(O)R^(d), wherein R^(iii) andR^(iv) are independently from each other H, methyl, or ethyl; wherein nis from 0 to 4; wherein R^(d) is C₁₋₆-alkoxy, —NR^(e)R^(f), whereinR^(e) and R^(f) are each independently hydrogen, C₁₋₆-alkyl, or—(C₂₋₆-alkylene)NR^(g)R^(h); wherein R^(g) and R^(h) are eachindependently hydrogen, C₁₋₆-alkyl, or —C(O)O—C₁₋₆-alkyl, phenyl, 5- to6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to7-membered cylcoalkyl, which are optionally substituted with one or moreA, —S(O)₂—C₁₋₆-alkyl, —S(O)₂N(C₁₋₆-alkyl)₂, —S(O)₂NH(C₁₋₆-alkyl); A ishalo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl, C₁₋₆-cyanoalkyl,C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, —S(O)₀₋₂C₁₋₆-alkyl, nitro, cyano,—(C₁₋₆-alkylene)-O—C₁₋₆-alkyl, —(C₁₋₆-alkylene)-OR′″, —C(O)OC₁₋₆-alkyl,—C(O)NR′R″, —S(O)₂NR′R″, —(CH₂)_(x)—NR′R″,—(CH₂)_(x)—NR′C(O)—C₁₋₆-alkyl, —(CH₂)_(x)—NR′S(O)₂—C₁₋₆-alkyl,—(CH₂)_(x)—C₃₋₆-cycloalkyl, —(CH₂)_(x)—R′″, wherein x is from 0 to 4, R′and R″ are each independently H or C₁₋₆-alkyl, or R′ and R″ togetherwith the nitrogen to which they are bound form a 5 or 6-memberedheterocycle comprising one or two heteroatoms selected from N, O and S,and R′″ is phenyl, optionally substituted with one, two, or three halo,C₁₋₆-haloalkyl, C₁₋₆-alkyl, or C₁₋₆-alkoxy.
 4. The compound of claim 1,wherein R² is hydrogen or C₁₋₆-alkyl.
 5. The compound of claim 1,wherein R³ and R⁶ are hydrogen.
 6. The compound of claim 1, wherein R¹is hydrogen.
 7. The compound of claim 1, wherein R¹ is C₁₋₁₂-alkyl,optionally substituted with CN or OH.
 8. The compound of claim 1,wherein R¹ is C₁₋₆-haloalkyl or C₂₋₁₂-alkenyl.
 9. The compound of claim1, wherein R¹ is —S(O)₂-phenyl, wherein phenyl is optionally substitutedwith one or more halo, C₁₋₆-haloalkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-haloalkoxy, nitro, hydroxy or cyano.
 10. The compound of claim 1,wherein R¹ is —S(O)₂—C₁₋₆-alkyl, —S(O)₂N(C₁₋₆-alkyl)₂, or—S(O)₂NH(C₁₋₆-alkyl).
 11. The compound of claim 1, wherein A is halo,C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl, C₁₋₆-cyanoalkyl,C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, C₁₋₆-thioalkyl, —S(O)₂—C₁₋₆-alkyl, cyano,—CH₂OCH₃, —C(O)O—C₁₋₆-alkyl, —C(O)NR′R″, —S(O)₂NR′R″,—NR'C(O)—C₁₋₆-alkyl, —NR′S(O)₂—C₁₋₆-alkyl, benzyl, or phenyl wherein R′and R″ are each independently H or C₁₋₆-alkyl.
 12. The compound of claim1, wherein R³, R⁴, R⁵, and R⁶ are each independently hydrogen, halo,C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, or C₁₋₆-haloalkoxy.
 13. Thecompound of claim 1, wherein R⁴ is hydrogen, Cl, F, or methyl.
 14. Thecompound of claim 1, wherein R⁵ is hydrogen, halo, CF₃, methoxy, or—OCF₃.
 15. The compound of claim 1, wherein R³ and R⁶ are hydrogen, R⁴is hydrogen, F, Cl or methyl, and R⁵ is halo, CF₃, methoxy or OCF₃. 16.The compound of claim 1, wherein R⁷, R⁸, R⁹, and R¹⁰ are eachindependently hydrogen, halo, C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁₋₆-alkoxy,or C₁₋₆-haloalkoxy.
 17. The compound of claim 1, selected from the groupconsisting of3-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-3H-benzooxazol-2-one,and2-{6-Chloro-3-[4-(2-oxo-benzooxazol-3-yl)-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide.18. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula I-b

wherein R¹ is H, C₁₋₁₂-alkyl, optionally substituted with CN or OH,C₁₋₆-haloalkyl, C₂₋₁₂-alkenyl, —(CR^(i)R^(ii))_(m)—R^(a), wherein R′ andR″ are independently from each other H, methyl, or ethyl; wherein m isfrom 0 to 4; wherein R^(a) is phenyl, 5- to 6-membered heteroaryl, 3- to7-membered heterocycloalkyl or 3 to 7-membered cylcoalkyl,  which areoptionally substituted with one or more A, or —NR^(b)R^(c), whereinR^(b) and R^(c) are each independently hydrogen, hydroxy,—S(O)₂—C₁₋₆-alkyl, or —C(O)—C₁₋₆-alkyl, —(CR^(iii)R^(iv))_(n)—C(O)R^(d),wherein R^(iii) and R^(iv) are independently from each other H, methyl,or ethyl; wherein n is from 0 to 4; wherein R^(d) is C₁₋₆-alkoxy,—NR^(e)R^(f), wherein R^(e) and R^(f) are each independently hydrogen,C₁₋₆-alkyl, or —(C₂₋₆-alkylene)NR^(g)R^(h); wherein R^(g) and R^(h) areeach independently hydrogen, C₁₋₆-alkyl, or —C(O)O—C₁₋₆-alkyl, phenyl,5- to 6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to7-membered cycloalkyl, which are optionally substituted with one or moreA, —S(O)₂-phenyl, wherein phenyl is optionally substituted with one ormore halo, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, nitro, hydroxyor cyano; —S(O)₂—C₁₋₆-alkyl, —S(O)₂N(C₁₋₆-alkyl)₂, —S(O)₂NH(C₁₋₆-alkyl);A is halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl,C₁₋₆-cyanoalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, —S(O)₀₋₂C₁₋₆-alkyl,nitro, hydroxy, cyano, —(C₁₋₆-alkylene)-O—C₁₋₆-alkyl,—(C₁₋₆-alkylene)-O—C₁₋₆-haloalkyl, —(C₁₋₆-alkylene)-OR′″,—C(O)OC₁₋₆-alkyl, —C(O)OR′″, —C(O)R′″, —C(O)NR′R″, —S(O)₂NR′R″,—(CH₂)_(x)—NR′R″, —(CH₂)_(x)—NR′C(O)—C₁₋₆-alkyl,—(CH₂)_(x)—NR′S(O)₂—C₁₋₆-alkyl, —(CH₂)_(x)—C₃₋₆-cycloalkyl,—(CH₂)_(x)—R′″, wherein x is from 0 to 4, R′ and R″ are eachindependently H or C₁₋₆-alkyl, or R′ and R″ together with the nitrogento which they are bound form a 5 or 6-membered heterocycle comprisingone or two heteroatoms selected from N, O and S, and R′″ is phenyl or 5-to 6-membered heteroaryl, optionally substituted with one, two, or threehalo, C₁₋₆-haloalkyl, C₁₋₆-alkyl, or C₁₋₆-alkoxy, R² is hydrogen,C₁₋₆-alkyl, —C(O)R^(n), wherein R^(n) is C₁₋₆-alkyl, 3 to 7-memberedheterocycloalkyl, optionally substituted with one, two or threeC₁₋₆-alkyl, —C(O)O—C₁₋₆-alkyl, or —S(O)₂—C₁₋₆-alkyl, NR^(j)R^(k),wherein R^(j) and R^(k) are each independently hydrogen, C₁₋₆-alkyl,—(C₂₋₆-alkylene)-NR^(l)R^(m); wherein R^(l) and R^(m) are eachindependently hydrogen, C₁₋₆-alkyl, or —C(O)O—C₁₋₆-alkyl; or R³, R⁴, R⁵,R⁶ are each independently hydrogen, halo, C₁₋₆-alkyl, halo-C₁₋₆-alkyl,C₁₋₆-alkoxy or C₁₋₆-haloalkoxy; R⁷, R⁸, R⁹, R¹⁰ are each independentlyhydrogen, halo, C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁₋₆-alkoxy orC₁₋₆-haloalkoxy; or a pharmaceutically acceptable salt thereof, with theproviso that compounds wherein R¹, R², R³, R⁴, R⁵ and R⁶ are allsimultaneously hydrogen are excluded.